MAO inhibiting N-benzyl-N-propargyl-amines useful for treating obesity

ABSTRACT

The invention provides novel N-benzyl-N-propargyl-amines that are monoamine oxidase inhibitors, but generally exhibit little or no CNS effects.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No. 60/886,715 filed Jan. 26, 2007. The disclosure this application is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides N-benzyl-N-propargyl-amines and pharmaceutical compositions thereof and methods of using the same for treating obesity. More particularly, the present invention relates to a novel method for treating obesity using an MAO inhibitor.

BACKGROUND OF THE INVENTION

Pargyline is a monoamine oxidase (MAO) inhibitor that was developed as an antihypertensive and later used for the treatment of neurological disorders. MAO is an enzyme responsible for metabolizing biogenic monoamines including serotonin, dopamine, histamine, and phenylethylamine. By inhibiting MAO located in the central nervous system (CNS), MAO inhibitors and their analogues increase the concentration of monoamines present within the brain synapses. This enhances monoamine-mediated neurotransmission, effectively treating neurological disorders such as Parkinson's disease and depression.

MAO enzymes are also located in a number of peripheral (non-CNS) tissues, including adipocytes; the cells that comprise body fat. The function of MAO enzymes in adipocytes has not been established. Currently, the only approved clinical use of L-selegiline and other MAO inhibitors is for the treatment of neurological disorders such as Parkinson's disease and depression.

Obesity is associated with an increase in the overall amount of adipose tissue (i.e., body fat), especially adipose tissue localized in the abdominal area. Obesity has reached epidemic proportions in the United States. The prevalence of obesity has steadily increased over the years among all racial and ethnic groups. According to the United States Surgeon General, 61% of the adult population and 14% of children are obese or overweight. Forty four million Americans are obese, with an additional eighty million deemed medically overweight. Obesity is responsible for more than 300,000 deaths annually, and will soon overtake tobacco usage as the primary cause of preventable death in the United States. Obesity is a chronic disease that contributes directly to numerous dangerous co-morbidities, including type 2 diabetes, cardiovascular disease, inflammatory diseases, premature aging, and some forms of cancer. Type 2 diabetes, a serious and life-threatening disorder with growing prevalence in both adult and childhood populations, is currently the 7^(th) leading cause of death in the United States. Since more than 80% of patients with type 2 diabetes are overweight, obesity is the greatest risk factor for developing type 2 diabetes. Increasing clinical evidence indicates that the best way to control type 2 diabetes is to reduce weight.

The most popular over-the counter drugs for the treatment of obesity, phenylpropanolamine and ephedrine, and the most popular prescription drug, fenfluramine, were removed from the marketplace as a result of safety concerns. Drugs currently approved for the long-term treatment of obesity fall into two categories: (a) CNS appetite suppressants such as sibutramine and (b) gut lipase inhibitors such as orlistat. CNS appetite suppressants reduce eating behavior through activation of the ‘satiety center’ in the brain and/or by inhibition of the ‘hunger center’ in the brain. Gut lipase inhibitors reduce the absorption of dietary fat from the gastrointestinal (GI) tract. Although sibutramine and orlistat work through very different mechanisms, they share in common the same overall goal of reducing body weight secondary to reducing the amount of calories that reach the systemic circulation. Unfortunately, these indirect therapies produce only a modest initial weight loss (approximately 5% compared to placebo) that is usually not maintained. After one or two years of treatment, most patients return to or exceed their starting weight. In addition, most approved anti-obesity therapeutics produce undesirable and often dangerous side effects that can complicate treatment and interfere with a patient's quality of life.

The lack of therapeutic effectiveness, coupled with the spiraling obesity epidemic, positions the ‘treatment of obesity’ as one of the largest and most urgent unmet medical needs. There is, therefore, a real and continuing need for the development of improved medications that treat obesity.

MAO inhibitors such as Pargyline have been clinically useful in the treatment of hypertension and CNS disorders. They have now unexpectedly been discovered to also have anti-obesity activity. Even more surprising is that the anti-obesity activity effects of these types of MAO inhibitors are mediated via a peripheral (i.e., non-CNS) mechanism. This new discovery provides a novel approach for the prevention or treatment of obesity. Moreover, if the CNS effects of these compounds can be reduced, their peripherally mediated anti-obesity properties should provide therapeutic agents with greater safety. It has, as a result, become highly desirable to find MAO inhibitors with limited or no CNS effects. Compounds of this sort are expected to be useful in treating obesity and the variety of co-morbidities to which it contributes.

SUMMARY OF THE INVENTION

Accordingly, in an aspect, the present invention provides novel MAO-B inhibitors or stereoisomers or pharmaceutically acceptable salts that are useful to treat obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance).

In another aspect, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides novel methods for treating obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance), comprising: administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides novel methods for treating CNS disorders, comprising: administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides processes for preparing novel compounds.

In another aspect, the present invention provides novel compounds or stereoisomers or pharmaceutically acceptable salts for use in therapy.

In another aspect, the present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of obesity, diabetes, and/or cardiometabolic disorders.

In another aspect, the present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of CNS disorders.

These and other aspects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the presently claimed compounds or stereoisomers or pharmaceutically acceptable salts thereof are expected to be effective MAO-B inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the unexpected finding that an MAO inhibitor is capable of reducing the amount of adipose tissue (i.e., body fat) in a warm-blooded mammal. This finding was unexpected because body fat can be reduced despite little, if any, concomitant reduction in food intake.

In an embodiment, the present invention provides novel compound AA or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein: A, A¹, A², A³, and A⁴ are selected from CH, CX, and N and at least one of Q, R¹, R², and X is a group capable of reducing or limiting the CNS activity of compound AA. Examples of compounds of formula II include compounds wherein: (a) at least one of: A-A⁴ is N; (b) R² is other than CH₃; and/or (c) at least one of Q, R¹, and X is other than H.

[1] In another embodiment, the present invention provides novel compounds of formula I or II or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

A, A¹, A², A³, and A⁴ are independently selected from CH, CX, and N;

R, at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R¹, at each occurrence, is independently selected from H, C₁₋₆ alkyl, (CH₂)_(m)CO₂R, C₂₋₆ alkenyl-CO₂R, (CH₂)₂CHMCONRCH₂CO₂R, CH₂CHMCONRCH₂CO₂R, CH₂CH(NHAc)CO₂R, CH₂CH(NHR)CO₂R, (CH₂)_(n)PO(OR)₂, (CH₂)₂CONRCH(OR)CO₂R, (CH₂)₂CONRC(R)₂CH₂SO₂OR, (CH₂)_(n)SO₂OR, and (CH₂)_(n)-tetrazole;

R², at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

X, at each occurrence, is independently selected from H, OH, OC₁₋₆ alkyl, OC₂₋₆ alkenyl, OC₂₋₆ alkynyl, O(CH₂CH₂O)_(q)R⁴, halogen, nitro, CF₃, (CH₂)_(m)CO₂R, CONRCH(L)CO₂R, CH═CHCO₂R, OCH₂CH═CHCO₂R, CH═CHCONRCH(L)CO₂R, C₆H₄CO₂R, C₆H₄CON(R)₂, C₆H₄CONRCH(L)CO₂R, O(CH₂)_(n)CO₂R, NR(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)CON(R)₂, CH₂OCH₂CH═CHCO₂R, CH₂OCH₂CO₂R, CH₂OCH₂PO(OR)₂, O—C₂₋₆ alkenyl-CO₂R, NR—C₃₋₆ alkenyl-CO₂R, N(R)₂, NRSO₂R^(a), SO₂NRCH₃, OCH₂CHMCONRCH₂CO₂R, NRCH₂CHMCONRCH₂CO₂R, NRCH₂CH(NHAc)CO₂R, O(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, NR(CH₂)_(n)SO₂OR, OCH₂(CH₂)_(n)N⁺(CH₃)₃V⁻, CH₂N⁺(CH₃)₃V⁻, O(CH₂)_(n)-aryl, NR(CH₂)_(n)-aryl, O(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and NR(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃.(CH₂)_(r)CO₂R³, (CH₂)_(r)SO₃H, (CH₂)_(r)PO₃H₂, (CH₂)_(r)PO₃RH, O(CH₂)_(r)CO₂R³, O(CH₂)_(r)SO₃H, O(CH₂)_(r)PO₃H₂, O(CH₂)_(r)PO₃RH, S(CH₂)_(r)CO₂R³S(CH₂)_(r)SO₃H, S(CH₂)_(r)PO₃H₂, S(CH₂)_(r)PO₃RH, (CH₂)_(r)CON(R³)₂, S(CH₂)_(n)CON(R³)₂, O(CH₂)_(n)CON(R³)₂, (CH₂)_(r)NR³SO₂R, (CH₂)_(r)C(═NR³)N(R³)₂, (CH₂)_(r)NR³C(═NR³)N(R³)₂, (CH₂)_(r)NR(C═NR³CN)N(R³)₂, (CH₂)_(r)NR³(C═CHNO₂)N(R³)₂, (CH₂)_(r)NR³C(═NR⁵)NR³R^(5a) (CH₂)_(r)tetrazol-5-yl, and O(CH₂CH₂O)_(q)R⁴;

R^(a), at each occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R³, at each occurrence, is independently is independently selected from H, C₁₋₆ alkyl, and benzyl;

R⁴, at each occurrence, is independently is independently selected from H, C₁₋₆ alkyl, (CH₂)_(n)aryl, and (CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S;

R⁵ and R^(5a) combine to form a —(CH₂)₂— or a —(CH₂)₃— group;

L, at each occurrence, is independently selected from H, C₁₋₆ alkyl, —(CH₂)_(n)-phenyl, —(CH₂)_(n)—O—C₁₋₆ alkyl, and —(CH₂)_(n)—S—C₁₋₆ alkyl, wherein the phenyl group is substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃. (CH₂)_(r)CO₂R³, (CH₂)_(r)SO₃H, (CH₂)_(r)PO₃H₂, (CH₂)_(r)PO₃RH, O(CH₂)_(r)CO₂R³, O(CH₂)_(r)SO₃H, O(CH₂)_(r)PO₃H₂, O(CH₂)_(r)PO₃RH, S(CH₂)_(r)CO₂R³, S(CH₂)_(r)SO₃H, S(CH₂)_(r)PO₃H₂, S(CH₂)_(r)PO₃RH, (CH₂)_(r)CON(R³)₂, S(CH₂)_(n)CON(R³)₂, O(CH₂)_(n)CON(R³)₂, (CH₂)_(r)NR³SO₂R, (CH₂)_(r)C(═NR³)N(R³)₂, (CH₂)_(r)NR³C(═NR³)N(R³)₂, (CH₂)_(r)NR³(C═NR³CN)N(R³)₂, (CH₂)_(r)NR³ (C═CHNO₂)N(R³)₂, (CH₂)_(r)NR³C(═NR⁵)NR³R^(1a), (CH₂)_(r)tetrazol-5-yl, and O(CH₂CH₂O)_(q)R⁴;

U is a counterion, but is absent when Z is O⁻;

V, at each occurrence, is a counterion;

Q, at each occurrence, is independently selected from H, C₁₋₆ alkyl, CO₂R, CH₂CO₂R, (CH₂)₃CO₂R, (CH₂)_(n)OR, CH₂O(CH₂CH₂O)_(q)R⁴, CH₂O(CH₂)_(n)-aryl, CH₂OC₃₋₆ alkenyl-CO₂R, CH₂NRC₃₋₆ alkenyl-CO₂R, (CH₂)_(n)O(CH₂)_(n)CO₂R, (CH₂)_(n)O(CH₂)_(n)CONH₂, (CH₂)_(n)OCH₂CHMCONRCH₂CO₂R, (CH₂)_(n)OCH₂CH(NHAc)CO₂R, (CH₂)_(n)OCH₂CH(NHR)CO₂R, (CH₂)_(n)O(CH₂)_(n)PO(OR)₂, (CH₂)_(n)O(CH₂)_(n)SO₂OR, (CH₂)_(n)O—C₂₋₆ alkenyl, (CH₂)_(n)O(CH₂)_(n)-aryl, (CH₂)_(n)O(CH₂)₂CONRCH(OR)CO₂R, (CH₂)_(n)O(CH₂)₂CONRC(R)₂CH₂SO₂OR, (CH₂)_(n)NRR, (CH₂)_(n)NR(CH₂)_(n)CO₂R, (CH₂)_(n)NR(CH₂)_(n)CONH₂, (CH₂)_(n)NRCH₂CHMCONRCH₂CO₂R, (CH₂)_(n)NRCH₂CH(NHAc)CO₂R, (CH₂)_(n)NRCH₂CH(NHR)CO₂R, (CH₂)_(n)NR(CH₂)_(n)PO(OR)₂, (CH₂)_(n)NR(CH₂)_(n)SO₂OR, (CH₂)_(n)NR(CH₂)_(n)-tetrazole, (CH₂)_(n)NR—C₂₋₆ alkenyl, (CH₂)_(n)NR(CH₂)_(n)-aryl, (CH₂)_(n)NR(CH₂)₂CONRC(R)₂CH₂SO₂OR, (CH₂)_(n)NR(CH₂)₂CONRCH(OR)CO₂R, (CH₂)_(n)NRCO(CH₂)_(n)CO₂R, and (CH₂)_(n)O(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃.(CH₂)_(r)CO₂R³ (CH₂)_(r)SO₃H, (CH₂)_(r)PO₃H₂, (CH₂)_(r)PO₃RH, O(CH₂)_(r)CO₂R, O(CH₂)_(r)SO₃H, O(CH₂)_(r)PO₃H₂, O(CH₂)_(r)PO₃RH, S(CH₂)_(r)CO₂R³, S(CH₂)_(r)SO₃H, S(CH₂)_(r)PO₃H₂, S(CH₂)_(r)PO₃RH, (CH₂)_(r)CON(R³)₂, S(CH₂)_(n)CON(R³)₂, O(CH₂)_(n)CON(R³)₂, (CH₂)_(r)NR³SO₂R, (CH₂)_(r)C(═NR³)N(R³)₂, (CH₂)_(r)NR³C(═NR³)N(R³)₂, (CH₂)_(r)NR³(C═NR³CN)N(R³)₂, (CH₂)_(r)NR³(C═CHNO₂)N(R³)₂, (CH₂)_(r)NR³C(═NR⁵)NR³R^(5a), (CH₂)_(r)tetrazol-5-yl, and O(CH₂CH₂O)_(q)R⁴;

M, at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, (CH₂)_(n)-aryl, 5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and (CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃. (CH₂)_(r)CO₂R³, (CH₂)_(r)SO₃H, (CH₂)_(r)PO₃H₂, (CH₂)_(r)PO₃RH, O(CH₂)_(r)CO₂R³, O(CH₂)_(r)SO₃H, O(CH₂)_(r)PO₃H₂, O(CH₂)_(r)PO₃RH, S(CH₂)_(r)CO₂R³, S(CH₂)_(r)SO₃H, S(CH₂)_(r)PO₃H₂, S(CH₂)_(r)PO₃RH, (CH₂)_(r)CON(R³)₂, S—(CH₂)_(n)CON(R³)₂, O—(CH₂)_(n)CON(R³)₂, (CH₂)_(r)NR³SO₂R, (CH₂)_(r)C(═NR³)N(R³)₂, (CH₂)_(r)NR³C(═NR³)N(R³)₂, (CH₂)_(r)NR³ (C═NR³CN)N(R³)₂, (CH₂)_(r)NR³ (C═CHNO₂)N(R³)₂, (CH₂)_(r)NR³C(═NR⁵)NR³R^(5a), (CH₂)_(r)tetrazol-5-yl, and O(CH₂CH₂O)_(q)R⁴;

Z, at each occurrence, is independently selected from O⁻, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)-aryl, and (CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S;

m, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

n, at each occurrence, is independently selected from 1, 2, 3, and 4;

q, at each occurrence, is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; and,

r, at each occurrence, is independently selected from 0, 1, 2, 3, and 4.

In another embodiment, the compounds of the present invention have from 0-1 acid functionalities.

[2] In another embodiment, the present invention provides novel compounds of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

A¹ and A² are independently selected from CH, CX, and N;

R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹, at each occurrence, is independently selected from (CH₂)_(m)CO₂R, C₂₋₆ alkenyl-CO₂R, (CH₂)₂CHMCONRCH₂CO₂R, CH₂CHMCONRCH₂CO₂R, CH₂CH(NHAc)CO₂R, CH₂CH(NHR)CO₂R, (CH₂)_(n)PO(OR)₂, (CH₂)₂CONRCH(OR)CO₂R, (CH₂)₂CONRC(R)₂CH₂SO₂OR, (CH₂)_(n)SO₂OR, and (CH₂)_(n)-tetrazole;

X, at each occurrence, is independently selected from H, OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, O(CH₂CH₂O)_(q)R⁴, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, O(CH₂)_(n)-aryl, NR(CH₂)_(n)-aryl, O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and NR(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴;

Q, at each occurrence, is independently selected from H, CH₃, (CH₂)_(n)OR, CH₂O(CH₂CH₂O)_(q)R⁴, CH₂O(CH₂)_(n)-aryl, (CH₂)_(n)O(CH₂)_(n)CONH₂, (CH₂)_(n)O—C₂₋₄ alkenyl, (CH₂)_(n)O(CH₂)_(n)-aryl, (CH₂)_(n)NRR, (CH₂)_(n)NR(CH₂)_(n)CONH₂, (CH₂)_(n)NR—C₂₋₄ alkenyl, (CH₂)_(n)NR(CH₂)_(n)-aryl, and (CH₂)_(n)O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴;

R⁴, at each occurrence, is independently selected from H, C₁₋₆ alkyl, (CH₂)_(n)aryl, and (CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S;

q, at each occurrence, is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; and,

M, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl, (CH₂)_(n)-aryl, 5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and (CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴.

[3] In another embodiment, the present invention provides novel compounds of formula Ib or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

A¹ and A² are independently selected from CH, CX, and N;

R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

X, at each occurrence, is independently selected from H, OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, O(CH₂CH₂O)_(q)R⁴, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, O(CH₂)_(n)-aryl, NR(CH₂)_(n)-aryl, O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and NR(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴;

Q, at each occurrence, is independently selected from H, CH₃, CO₂R, CH₂CO₂R, (CH₂)₃CO₂R, (CH₂)_(n)OOR, CH₂O(CH₂CH₂O)_(q)R⁴, CH₂O(CH₂)_(n)-aryl, CH₂OCH₂CH═CHCO₂R, CH₂NHCH₂CH═CHCO₂R, (CH₂)_(n)O(CH₂)_(n)CO₂R, (CH₂)_(n)O(CH₂)_(n)CONH₂, (CH₂)_(n)OCH₂CHMCONRCH₂CO₂R, (CH₂)_(n)OCH₂CH(NHAc)CO₂R, (CH₂)_(n)OCH₂CH(NHR)CO₂R, (CH₂)_(n)O(CH₂)_(n)PO(OR)₂, (CH₂)_(n)O(CH₂)_(n)SO₂OR, (CH₂)_(n)O(CH₂)_(n)-tetrazole, (CH₂)_(n)O(CH₂)₂CONRCH(OR)CO₂R, (CH₂)_(n)O(CH₂)₂CONRC(R)₂CH₂SO₂OR, (CH₂)_(n)NR(CH₂)_(n)CO₂R, (CH₂)_(n)NR(CH₂)_(n)CONH₂, (CH₂)_(n)NRCH₂CHMCONRCH₂CO₂R, (CH₂)_(n)NRCH₂CH(NHAc)CO₂R, (CH₂)_(n)NRCH₂CH(NHR)CO₂R, (CH₂)_(n)NR(CH₂)_(n)PO(OR)₂, (CH₂)_(n)NR(CH₂)_(n)SO₂OR, (CH₂)_(n)NR(CH₂)_(n)-tetrazole, (CH₂)_(n)NR(CH₂)₂CONRC(R)₂CH₂SO₂OR, (CH₂)_(n)NRCO(CH₂)_(n)CO₂R, (CH₂)_(n)O(CH₂)_(n)-aryl, and (CH₂)_(n)O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from NRSO₂CH₃, SO₂NRCH₃. (CH₂)_(r)CO₂R, (CH₂)_(r)SO₃H, (CH₂)_(r)PO₃H₂, (CH₂)_(r)PO₃RH, O(CH₂)_(r)CO₂R³, O(CH₂)_(r)SO₃H, O(CH₂)_(r)PO₃H₂, O(CH₂)_(r)PO₃RH, S(CH₂)_(r)CO₂R³S(CH₂)_(r)SO₃H, S(CH₂)_(r)PO₃H₂, S(CH₂)_(r)PO₃RH, (CH₂)_(r)CON(R³)₂, S(CH₂)_(n)CON(R³)₂, O(CH₂)_(n)CON(R³)₂, (CH₂)_(r)NR³SO₂R, (CH₂)_(r)C(═NR³)N(R³)₂, (CH₂)_(r)NR³C(═NR³)N(R³)₂, (CH₂)_(r)NR³(C═NR³CN)N(R³)₂, (CH₂)_(r)NR³ (C═CHNO₂)N(R³)₂, (CH₂)_(r)NR³C(═NR⁵)NR³R^(5a), (CH₂)_(r)tetrazol-5-yl, and O(CH₂CH₂O)_(q)R⁴; and,

M, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl, (CH₂)_(n)-aryl, 5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and (CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴.

[4] In another embodiment, the present invention provides novel compounds of formula Ic or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

Q, at each occurrence, is independently selected from H, CH₃, (CH₂)_(n)OR, CH₂O(CH₂CH₂O)_(q)R⁴, CH₂O(CH₂)_(n)-aryl, (CH₂)_(n)O(CH₂)_(n)CONH₂, (CH₂)_(n)O—C₂₋₄ alkenyl, (CH₂)_(n)O(CH₂)_(n)-aryl, and (CH₂)_(n)O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, O(CH₂CH₂O)_(q)R⁴O(CH₂)_(r)CO₂R³, O(CH₂)_(r)SO₃H, O(CH₂)_(r)PO₃H₂, O(CH₂)_(r)PO₃RH, S(CH₂)_(r)CO₂R³, S(CH₂)_(r)SO₃H, S(CH₂)_(r)PO₃H₂, and S(CH₂)_(r)PO₃RH;

X, at each occurrence, is independently selected from H, (CH₂)_(m)CO₂R, CONRCH(L)CO₂R, CH═CHCO₂R, OCH₂CH═CHCO₂R, CH═CHCONRCH(L)CO₂R, C₆H₄CO₂R, C₆H₄CONRCH(L)CO₂R, O(CH₂)_(n)CO₂R, NR(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)CON(R)₂, CH₂OCH₂CH═CHCO₂R, CH₂OCH₂CO₂R, CH₂OCH₂PO(OR)₂, O—C₂₋₆ alkenyl-CO₂R, NR—C₃₋₆ alkenyl-CO₂R, N(R)₂, NRSO₂R^(a), SO₂NRCH₃, OCH₂CHMCONRCH₂CO₂R, NRCH₂CHMCONRCH₂CO₂R, NRCH₂CH(NHAc)CO₂R, O(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, NR(CH₂)_(n)SO₂OR, O(CH₂CH₂O)_(q)R⁴, OCH₂(CH₂)_(n)N⁺(CH₃)₃V⁻, CH₂N⁺(CH₃)₃V⁻, O(CH₂)_(n)-aryl, NR(CH₂)_(n)-aryl, and O(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from NRSO₂CH₃, SO₂NRCH₃. (CH₂)_(r)CO₂R³, (CH₂)_(r)SO₃H, (CH₂)_(r)PO₃H₂, (CH₂)_(r)PO₃RH, (CH₂)_(r)CON(R³)₂, S—(CH₂)_(n)CON(R³)₂, O—(CH₂)_(n)CON(R³)₂, (CH₂)_(r)NR³SO₂R, (CH₂)_(r)C(═NR³)N(R³)₂, (CH₂)_(r)NR³C(═NR³)N(R³)₂, (CH₂)_(r)NR³(C═NR³CN)N(R³)₂, (CH₂)_(r)NR³ (C═CHNO₂)N(R³)₂, (CH₂)_(r)NR³C(═NR⁵)NR³R^(5a), (CH₂)_(r)tetrazol-5-yl, and O(CH₂CH₂O)_(q)R⁴, provided that at least one X is other than H;

R³, at each occurrence, is independently selected from H, C₁₋₆ alkyl, and benzyl;

R⁴, at each occurrence, is independently selected from H, C₁₋₆ alkyl, (CH₂)_(n)aryl, and (CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S;

q, at each occurrence, is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

R⁵ and R^(5a) combine to form a —(CH₂)₂— or a —(CH₂)₃— group;

L, at each occurrence, is independently selected from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, (CH₂)₂SCH₃, and benzyl;

M, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl, (CH₂)_(n)-aryl, 5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and (CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴; and,

V, at each occurrence, is Cl or Br.

[5] In another embodiment, the present invention provides novel compounds of formula IIa or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

A¹ and A² are independently CH or CX;

R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

Q, at each occurrence, is independently selected from H, CH₃, (CH₂)_(n)OR, CH₂O(CH₂)_(n)-aryl, (CH₂)_(n)O(CH₂)_(n)CONH₂, (CH₂)_(n)O—C₂₋₄ alkenyl, and (CH₂)_(n)O(CH₂)_(n)-aryl, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴;

X, at each occurrence, is independently selected from H, OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, O(CH₂CH₂O)_(q)R⁴O(CH₂)_(n)-aryl, and O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴;

Z is selected from O⁻, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, (CH₂)_(n)-aryl, and (CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; and,

U is Cl or Br, but is absent when Z is O⁻.

In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method for treating a disease, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof.

In another embodiment, the cardiometabolic disorder is selected from hypertension, dyslipidemias (e.g., undesirable blood lipid levels, elevated cholesterol levels, and lowered LDL levels), high blood pressure, and insulin resistance.

In another embodiment, the present invention provides a novel method for treating a co-morbidity of obesity, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, the co-morbidity is selected from diabetes, Metabolic Syndrome, dementia, and heart disease.

In another embodiment, the co-morbidity is selected from hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous statis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arterial sclerotic disease; pseudotumor cerebri; accident proneness; increased risks with surgeries; osteoarthritis; high cholesterol; and, increased incidence of malignancies of the ovaries, cervix, uterus, breasts, prostrate, and gallbladder.

In another embodiment, the present invention provides a novel method for treating a CNS disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, the CNS disorder is selected from acute and chronic neurological disorders, cognitive disorders, and memory deficits. Examples of these disorders include chronic or traumatic degenerative processes of the nervous system, which include Alzheimer's disease, other types of dementia, minimal cognitive impairment, and Parkinson's disease. Other examples of CNS disorders include psychiatric diseases, which include depression, anxiety, panic attack, social phobia, schizophrenia, and anorexia. Further examples of CNS disorders include withdrawal syndromes induced by alcohol, nicotine and other addictive drugs. Additional examples of CNS disorders include neuropathic pain and neuroinflamatory diseases (e.g., multiple sclerosis).

In another embodiment, the present invention also provides a method of preventing or reversing the deposition of adipose tissue in a mammal by the administration of a MAO-B inhibitor. By preventing or reversing the deposition of adipose tissue, MAO-B inhibitors are expected to reduce the incidence or severity of obesity, thereby reducing the incidence or severity of associated co-morbidities.

In another embodiment, the present invention provides a compound of the present invention for use in therapy.

In another embodiment, the present invention provides the use of compounds of the present invention for the manufacture of a medicament for the treatment of obesity, diabetes, cardiometabolic disorders, and a combination thereof.

In another embodiment, the present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of CNS disorders.

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is intended to be taken individually as its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

Definitions

The examples provided in the definitions present in this application are non-inclusive unless otherwise stated. They include but are not limited to the recited examples.

Acid functionalities include carboxylic acids, carboxylic acid esters, tetrazole, SO₂OR³, and PO(OR³)₂.

The compounds herein described may have asymmetric centers, geometric centers (e.g., double bond), or both. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or through use of chiral auxiliaries. Geometric isomers of olefins, C═N double bonds, or other types of double bonds may be present in the compounds described herein, and all such stable isomers are included in the present invention. Specifically, cis and trans geometric isomers of the compounds of the present invention may also exist and may be isolated as a mixture of isomers or as separated isomeric forms. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described compounds are also considered to be part of the present invention.

The present invention includes all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Examples of the molecular weight of the compounds of the present invention include (a) less than about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 grams per mole; (b) less than about 950 grams per mole; (c) less than about 850 grams per mole; and, (d) less than about 750 grams per mole.

“Alkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C₁₋₆ alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Alkenyl” includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, and C₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C₂₋₆ Alkynyl includes C₂, C₃, C₄, C₅, and C₆ alkynyl groups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in a saturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃, C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

“Alkoxy” represents an alkyl group as defined above with the indicated number of hydrocarbon atoms attached through an oxygen bridge. C₁₋₆ alkoxy, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Counterion” is used to represent a small, negatively charged species, such as chloride, bromide, hydroxide, acetate, and sulfate.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 membered monocyclic, bicyclic, or tricyclic ring, wherein at least one ring, if more than one is present, is aromatic. Examples of aryl include fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

The group “C₆H₄” represents a phenylene.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 membered monocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic, and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. If the heteroaryl group is bicyclic or tricyclic, then at least one of the two or three rings must contain a heteroatom, though both or all three may each contain one or more heteroatoms. If the heteroaryl group is bicyclic or tricyclic, then only one of the rings must be aromatic. The N group may be N, NH, or N-substituent, depending on the chosen ring and if substituents are recited. The nitrogen and sulfur heteroatoms may optionally be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heteroaryl ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heteroaryl rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.

Examples of heteroaryl includes acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

Preventing the deposition of adipose tissue covers methods of treating wherein the levels of adipose tissue of a subject remain about the same as prior to being treated in accordance with the present invention (i.e., its pre-administration level) or not more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% greater than pre-administration level (particularly when the subject is pre-disposed to increasing adipose tissue levels).

Reversing the deposition of adipose tissue covers methods of treating wherein the levels of adipose tissue of a subject are lower than those prior to being treated in accordance with the present invention (i.e., its pre-administration level). Examples of lower include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20% or more lower than pre-administration level.

Mammal and patient covers warm blooded mammals that are typically under medical care (e.g., humans and domesticated animals). Examples of mammals include (a) feline, canine, equine, bovine, and human and (b) human.

“Treating” or “treatment” covers the treatment of a disease-state in a mammal, and includes: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, e.g., arresting it development; and/or (c) relieving the disease-state, e.g., causing regression of the disease state until a desired endpoint is reached. Treating also includes the amelioration of a symptom of a disease (e.g., lessen the pain or discomfort), wherein such amelioration may or may not be directly affecting the disease (e.g., cause, transmission, expression, etc.).

“Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p 1445, the disclosure of which is hereby incorporated by reference.

“Therapeutically effective amount” includes an amount of a compound of the present invention that is effective when administered alone or in combination to treat obesity or another indication listed herein. “Therapeutically effective amount” also includes an amount of the combination of compounds claimed that is effective to treat the desired indication. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased effect, or some other beneficial effect of the combination compared with the individual components.

Utility

Obesity is defined as having a body mass index (BMI) of 30 or above. The index is a measure of an individual's body weight relative to height. BMI is calculated by dividing body weight (in kilograms) by height (in meters) squared. Normal and healthy body weight is defined as having a BMI between 20 and 24.9. Overweight is defined as having a BMI of 25 or above. Obesity has reached epidemic proportions in the U.S., with 44 million obese Americans, and an additional eighty million deemed medically overweight.

Obesity is a disease characterized as a condition resulting from the excess accumulation of adipose tissue, especially adipose tissue localized in the abdominal area. It is desirable to treat overweight or obese patients by reducing their amount of adipose tissue, and thereby reducing their overall body weight to within the normal range for their sex and height. In this way, their risk for co-morbidities such as diabetes and cardiovascular disease will be reduced. It is also desirable to prevent normal weight individuals from accumulating additional, excess adipose tissue, effectively maintaining their body weights at a BMI <25, and preventing the development of co-morbidities. It is also desirable to control obesity, effectively preventing overweight and obese individuals from accumulating additional, excess adipose tissue, reducing the risk of further exacerbating their co-morbidities.

There exist two forms of MAO, designated MAO-A and MAO-B. The two forms differ with respect to substrate and inhibitor specificities and amino acid number and sequence. A preferred substrate for MAO-B is beta-phenylethylamine. In contrast, a preferred substrate for MAO-A is serotonin. Some MAO inhibitors show selectivity for MAO-A or for MAO-B, whereas other MAO inhibitors show little, if any selectivity. For example, the MAO inhibitor clorgyline preferentially inhibits MAO-A; the MAO inhibitor L-selegiline preferentially inhibits MAO-B; and, the MAO inhibitor iproniazid is non-selective (i.e., has a similar affinity for both). Examples of selectivity include a compound having about 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more fold higher affinity for one form of MAO than for the other form. One of ordinary skill in the art recognizes that there can be some difficulty in classifying MAO inhibitors. Some compounds may selectively inhibit one form of MAO in vitro and then lose their selectivity in vivo. Also, selectivity of a compound may vary from species to species or from tissue to tissue. In the context of the present invention, it is desirable to inhibit MAO-B activity in vivo in a mammal. Thus, selectivity and affinity are based on the in vivo activity of the MAO inhibitor and the mammalian species to which it is being or to be administered. Examples of the selectivity of a MAO-B inhibitor of the present invention include (a) at least a 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, to 100-fold greater affinity for MAO-B than MAO-A in the mammalian species (e.g., human) to be treated and (b) at least 100-fold greater affinity for MAO-B than MAO-A in the mammalian species (e.g., human) to be treated.

Some of the compounds of the present invention have been designed to have reduced CNS exposure by virtue of their inability or limited ability to penetrate the blood-brain barrier (e.g., quaternary salts or acid substituents) or by their participation in active transport systems, thus reducing centrally mediated side-effects, a potential problem with many anti-obesity agents.

Other compounds of the present invention are expected to penetrate the blood-brain barrier and therefore also be useful to treat CNS disorders (e.g., Parkinson's disease, depression, and Alzheimer's disease).

MAO enzymes are also located in a number of peripheral (non-CNS) tissues, including adipose tissue, muscle and liver. In order to treat non-CNS disorders (e.g., obesity, diabetes, and/or cardiometabolic disorders), it is necessary to administer enough of a drug sufficient to inhibit MAO in peripheral tissues. MAO inhibitors in use today to treat various psychiatric and neurological diseases, regardless of route of administration, enter the CNS from the systemic circulation. While present in the systemic circulation, such drugs have access to peripheral tissues, including adipose tissue, liver, and muscle. One of skill in the art recognizes that MAO inhibitors intended to enter the CNS from the systemic circulation in order to treat psychiatric and neurological diseases also have access to MAO in peripheral tissues, including adipose tissue, liver, and muscle. Thus, an MAO inhibitor useful for treating non-CNS disorders may have some access to the CNS from the systemic circulation.

Drugs enter the CNS from the systemic circulation by crossing the blood-brain barrier (BBB). The BBB is a highly specialized ‘gate-keeper’ that protects the brain by preventing the entry of many potentially harmful substances into the CNS from the systemic circulation. Much is known about the BBB, and of the physical-chemical properties required for compounds transported across it.

Drugs that do not cross the BBB into the CNS or that are readily eliminated through transport mechanisms (J Clin Invest. 97, 2517 (1996)) are known in the literature and have low CNS activity due to their inability to develop brain levels necessary for pharmacological action. The BBB has at least one mechanism to remove drugs prior to their accumulation in the CNS. P-Glycoproteins (P-gp) localized in plasma membrane of the BBB can influence the brain penetration and pharmacological activity of many drugs through translocation across membranes. The lack of accumulation into the brain by some drugs can be explained by their active removal from the brain by P-gp residing in the BBB. For example, the typical opioid drug loperamide, clinically used as an antidiarrheal, is actively removed from the brain by P-gp, thus explaining its lack of opiate-like CNS effects. Another example is domperidone, a dopamine receptor blocker that participates in the P-gp transport (J Clin Invest. 97, 2517 (1996)). Whereas dopamine receptor blockers that cross the BBB can be used to treat schizophrenia, the readily-eliminated domperidone can be used to prevent emesis, without the likelihood of producing adverse CNS effects.

In addition to the above compounds, agents possessing structural characteristics that retard or prevent BBB penetration or contribute to participation in active elimination processes have been identified in various classes of therapeutics. These include antihistamines (Drug Metab. Dispos. 31, 312 (2003)), beta-adrenergic receptor antagonists (B-blockers)(Eur. J. Clin. Pharmacol. 28, Suppl: 21-3 (1985); Br. J. Clin. Pharmacol., 11 (6), 549-553 (1981)), non-nucleoside reverse transcriptase inhibitors (NNRTIs)(J. Pharm Sci., 88(10) 950-954 (1999)), and opioid antagonists. This latter group has been tested in relation to their activity in the GI tract. These peripherally selective opioid antagonists are described in various US patents as being useful in the treatment of non-CNS pathologies in mammals, in particular those of the GI tract (see U.S. Pat. Nos. 5,260,542; 5,434,171; 5,159,081; and 5,270,238).

Other types of non-brain penetrant compounds can be prepared through the creation of a charge within the molecule. Thus, the addition of a methyl group to the tertiary amine functionality of the drugs scopolamine or atropine, unlike the parent molecules, prevents their passage across the BBB through the presence of a positive charge. However, the new molecules (methyl-scopolamine and methyl-atropine) retain their full anticholinergic pharmacological properties. As such, these drugs can also be used to treat peripheral diseases, without the concern of adverse CNS effects. The quaternary ammonium compound methylnaltrexone is also used for the prevention and/or treatment of opioid and non-opioid induced side effects associated with opioid administration.

MAO-B inhibitors such as Pargyline have been useful in the treatment of hypertension and CNS disorders. The unexpected discovery that the anti-obesity activity mediated by these agents is mediated by a non-CNS mechanism makes it preferable that the compounds of the present invention be peripherally restricted, i.e., have an inability or limited ability to cross the BBB or be readily eliminated from the brain through active transport systems. It is expected that the peripherally restricted compounds of the present invention will have no or very limited CNS effects. Thus, their peripherally mediated anti-obesity properties will provide therapeutic agents with greater safety, as previously demonstrated in earlier classes of peripherally restricted agents. It is preferred that the compounds of the present invention, when administered in a therapeutically effective amount, have no or very limited CNS effects. It is also preferred that the lack of CNS effects is a result of the compounds of the present invention having minimal brain concentrations when administered in therapeutically effective amounts. In this context, minimal brain concentrations means levels that are too low to be therapeutically effective for the treatment of a CNS indication or too low to cause significant or measurable deleterious or undesired side effects.

Compound AA is Pargyline when R¹ is CH₃; A-A⁴ are all CH; and, Q and R² are all H. Pargyline is a drug that crosses the BBB and is indicated for the treatment of hypertension. In compound AA, one of R, R¹, R², X, X¹, and Z is a group capable of reducing or limiting the CNS activity of compound AA. This reduced or limited CNS activity occurs via at least one of R, R¹, R², X, X¹, and Z being a group that either limits compound AA's ability to cross the BBB relative to that of Pargyline or enables it to be actively removed at a rate greater than that of Pargyline. Examples of brain levels of compound A include levels that are (a) from 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than Pargyline, when administered at the same dosage; (b) from 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than Pargyline, when administered at the same dosage; and, (c) from 98, 99, to 100% lower than Pargyline, when administered at the same dosage.

Most methods of treating obesity are dependent on a significant reduction in energy intake, either by a decrease in food intake (e.g., sibutramine) or by inhibition of fat absorption (e.g., orlistat). In the present invention, it can be desirable for adipose tissue to be significantly reduced in the absence of a significant reduction in food intake. The weight loss, as a result of the present invention, comes from the treatment with an MAO-B inhibitor, largely independent of appetite and food intake. Examples of the level of food intake during adipose tissue loss include (a) food intake is maintained, increased or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) food intake is maintained, increased, or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below its pre-administration level; (c) food intake is maintained, increased or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below its pre-administration level; and (d) food intake level is maintained, increased or about 0, 1, 2, 3, 4, or 5% below its pre-administration level.

In some cases, loss of adipose tissue can be accompanied by a concomitant loss of lean muscle mass. This is particularly evident in cancer patients who show a wasting of all body tissue components, including adipose tissue and lean muscle mass. In the present invention, however, it can be desirable for body fat to be significantly reduced in the absence of a significant reduction in lean body mass. Adipose tissue loss comes from treatment with an MAO-B inhibitor, independent of a significant change in lean body mass. Examples of the level of lean body mass during adipose tissue loss include (a) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels; (c) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels; and (d) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, or 5% below pre-administration levels.

In some cases, loss of adipose tissue can be accompanied by a concomitant loss of water mass. This is particularly evident with diet regimens that promote dehydration. In the present invention, it can be desirable for body fat to be significantly reduced in the absence of a significant reduction in water mass. In other words, adipose tissue loss comes from treatment with an MAO-B inhibitor, independent of a significant change in water mass. Examples of the level of water mass during adipose tissue loss include (a) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels; (c) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels; and (d) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, or 5% below pre-administration levels.

Sibutramine and orlistat are currently marketed for use in the treatment of obesity. These two compounds achieve weight loss through entirely different mechanisms. Sibutramine, a CNS appetite suppressant, inhibits the neuronal reuptake of serotonin and noradrenaline. Orlistat inhibits gut lipase enzymes that are responsible for breaking down ingested fat.

The mechanism of action of MAO-B inhibitors is believed to be entirely different from appetite suppressants, gut lipase inhibitors, and other agents with similar indications (e.g., serotonin agonists, leptin, and fatty acid synthase inhibitors). Co-administration of a MAO-B inhibitor together with one or more other agents that are useful for treating the indications described above (e.g., obesity, diabetes, cardiometabolic disorders, and a combination thereof) is expected to be beneficial, by producing, for example, either additive or synergistic effects. Examples of additional agents include an appetite suppressant and a lipase inhibitor. Therefore, the present invention provides a method of treating obesity, diabetes, and/or cardiometabolic disorders, comprising administering a therapeutically effective amount of a compound of the present invention and a second component selected from an appetite suppressant (e.g., sibutramine, phentermine, fenfluramine) and a gut lipase inhibitor (e.g., orlistat).

MAO-B inhibitors are expected to promote weight loss without appreciably reducing caloric intake. Co-administration of an MAO-B inhibitor together with an appetite suppressant is expected to produce either additive or synergistic effects on weight loss. Similarly, co-administration of an MAO-B inhibitor together with a lipase inhibitor is expected to produce either additive or synergistic effects on weight loss.

The ability of compounds to inhibit MAOs can be determined using the method of R. Uebelhack et al., Pharmacopsychiatry 31, 187-192 (1988)(as described below).

Preparation of Platelet-Rich Plasma and Platelets. Venous Blood from healthy subjects was collected between 8 and 8.30 a.m. after an overnight fast into EDTA-containing vacutainer tubes (11.6 mg EDTA/ml blood). After centrifugation of the blood at 250×g for 15 minutes at 20° C., the supernatant platelet-rich plasma (PRP) was collected and the number of platelets in PRP counted with a cell counter (MOIAB, Hilden, Germany). 2 ml of PRP was spun at 1500×g for 10 min to yield a platelet pellet. The pellet was washed three times with ice-cold saline, resuspended in 2 ml Soerensen phoshate buffer, pH 7.4 and stored at −18° C. for one day.

MAO assay. Fresh PRP or frozen platelet suspension (100 μL) was generally preincubated for 10 min in the absence or presence of drugs at 37° C. in 100 uL of 0.9% NaCl solution or phosphate buffer pH 7.4, respectively, at 37° C. 50 μL of 2-phenylethylamine-[ethyl-1-14C]hydrochloride (PEA) solution (specific activity 56 Ci/mol, Amersham) was then added in a final concentration of 5 μM, and the incubation was continued for 30 min. The reaction was terminated by the addition of 50 μL of 4M HClO₄. The reaction product of MAO, phenylacetaldehyde, was extracted into 2 mL of n-hexane. An aliquot of the organic phase was added to scintillator cocktail and the radioactivity was determined using a liquid scintillation counter. Product formation was linear with time for at least 60 min with appropriate platelet numbers. Blank values were obtained by including 2 mM pargyline in the incubation mixtures. All assays were performed in duplicate.

The ability of compounds to inhibit MAO activity can also be determined using the following method. cDNA's encoding human MAO-B can be transiently transfected into EBNA cells using the procedure described by E.-J. Schlaeger and K. Christensen (Transient Gene Expression in Mammalian Cells Grown in Serum-free Suspension Culture; Cytotechnology, 15: 1-13, 1998). After transfection, cells are homogeneized by means of a Polytron homogeneiser in 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA and 0.5 mM phenylmethanesulfonyl fluoride. Cell membranes are obtained by centrifugation at 45,000×g and, after two rinsing steps with 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA, membranes are eventually re-suspended in buffer and aliquots stored at −80° C. until use.

MAO-B enzymatic activity can be assayed using a spectrophotometric assay adapted from the method described by M. Zhou and N. Panchuk-Voloshina (A One-Step Fluorometric Method for the Continuous Measurement of Monoamine Oxidase Activity, Analytical Biochemistry, 253: 169-174, 1997). Briefly, membrane aliquots are incubated in 0.1 M potassium phosphate buffer, pH 7.4, for 30 min at 37° C. with or without various concentrations of the compounds. After incubation, the enzymatic reaction is started by the addition of the MAO substrate tyramine together with 1 U/ml horse-radish peroxidase (Roche Biochemicals) and 80 μM N-acetyl-3,7,-dihydroxyphenoxazine (Amplex Red, Molecular Probes). The samples are further incubated for 30 min at 37° C. in a final volume of 200 μl and absorbance is determined at a wavelength of 570 nm using a SpectraMax plate reader (Molecular Devices). Background (non-specific) absorbance is determined in the presence of 10 μM L-deprenyl for MAO-B. IC₅₀ values are determined from inhibition curves obtained using nine inhibitor concentrations in duplicate, by fitting data to a four parameter logistic equation.

Compounds of the present invention are expected to be MAO-B inhibitors. Representative compounds have been tested, as measured in the assay described herein, and have been shown to be active as their IC₅₀ values were found to be in the range of ≦10 μM. Compounds of the present invention are considered to be MAO-B inhibitors if they have an IC₅₀ value less than or equal to 10 μM. Additional examples of desirable activity levels of MAO-B inhibitors useful in the present invention include (a) an IC₅₀ value of 1 μM or lower, (b) an IC₅₀ value of 0.1 μM or lower, (c) an IC₅₀ value of 0.01 μM or lower, (d) an IC₅₀ value of 0.001 μM or lower, and (e) an IC₅₀ value of 0.0001 μM or lower.

In the present invention, MAO-B inhibitor(s) can be administered enterally, parenterally, orally, and transdermally. One skilled in this art is aware that the routes of administering the compounds of the present invention may vary significantly. In addition to other oral administrations, sustained release compositions may be favored. Other examples of routes include injections (e.g., intravenous, intramuscular, and intraperitoneal); subcutaneous; subdermal implants; buccal, sublingual, topical (e.g., a dermal or transdermal patch), rectal, vaginal, and intranasal administrations. Bioerodible, non-bioerodible, biodegradable, and non-biodegradable systems of administration may also be used.

If a solid composition in the form of tablets is prepared, the main active ingredient can be mixed with a pharmaceutical vehicle, examples of which include silica, starch, lactose, magnesium stearate, and talc. The tablets can be coated with sucrose or another appropriate substance or they can be treated so as to have a sustained or delayed activity and so as to release a predetermined amount of active ingredient continuously. Gelatin capsules can be obtained by mixing the active ingredient with a diluent and incorporating the resulting mixture into soft or hard gelatin capsules. A syrup or elixir can contain the active ingredient in conjunction with a sweetener, which is preferably calorie-free, an antiseptic (e.g., methylparaben and/or propylparaben), a flavoring, and an appropriate color. Water-dispersible powders or granules can contain the active ingredient mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors. Rectal administration can be effected using suppositories, which are prepared with binders melting at the rectal temperature (e.g., cocoa butter and/or polyethylene glycols). Parenteral administration can be effected using aqueous suspensions, isotonic saline solutions, or injectable sterile solutions, which contain pharmacologically compatible dispersants and/or wetting agents (e.g., propylene glycol and/or polyethylene glycol). The active ingredient can also be formulated as microcapsules or microspheres, optionally with one or more carriers or additives. The active ingredient can also be presented in the form of a complex with a cyclodextrin, for example α-, β-, or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and/or methyl-β-cyclodextrin.

The dose of the MAO-B inhibitor administered daily will vary on an individual basis and to some extent may be determined by the severity of the disease being treated (e.g., obesity). The dose of the MAO-B inhibitor will also vary depending on the MAO-B inhibitor administered. An example of a range of dosages of an MAO-B inhibitor is about from 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 76, 80, 85, 90, 95, to 100 mg/kg of mammal body weight. The MAO-B inhibitor can be administered in a single dose or in a number of smaller doses over a period of time. The length of time during which the MAO-B inhibitor is administered varies on an individual basis, and can continue until the desired results are achieved (i.e., reduction of body fat, or prevention of a gain in body fat). Therapy could, therefore, last from 1 day to weeks, months, or even years depending upon the subject being treated, the desired results, and how quickly the subject responds to treatment in accordance with the present invention.

A possible example of a tablet of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 100 Powdered lactose 95 White corn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2 Tablet weight 250

A possible example of a capsule of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 50 Crystalline lactose 60 Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150

In the above capsule, the active ingredient has a suitable particle size. The crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved, and thereafter the talc and magnesium stearate are admixed. The final mixture is filled into hard gelatin capsules of suitable size.

A possible example of an injection solution of the present invention is as follows.

Ingredient mg/Tablet Active substance 1.0 mg 1 N HCl 20.0 μl acetic acid 0.5 mg NaCl 8.0 mg Phenol 10.0 mg 1 N NaOH q.s. ad pH 5 H₂O q.s. ad 1 mL Synthesis

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.

The nitrobenzaldehyde of Scheme 1 can be reductively aminated using N-methyl-N-propargylamine and sodium cyanoborohydride under slightly acidic conditions to provide the tertiary benzyl amine (step a). The nitro group can then be reduced using sodium dithionite in aqueous dioxane containing concentrated ammonium hydroxide solution (step b). Further treatment of this aniline with methanesulfonyl chloride should produce the sulfonamide (step c). Alternatively, the aniline can be deprotonated with base and subsequently treated with an ethyl bromoacetate (step c) or bromoacetamide (step d) to yield the amino ester or the amino acetamide, respectively.

The amino acid ester shown in Scheme 2 can be N-alkylated using formalin and sodium cyanoborohydride under slightly acidic conditions to provide the N-methylated ester (step a). The secondary amine could be alkylated with propargyl bromide to give the tertiary amino ester (step b). Hydrolysis of the ester using aqueous LiOH solution in a co-solvent can produce the amino acid (step c).

Alternatively, if the tertiary amino ester is reduced with lithium aluminum hydride (LAH), the primary alcohol can be produced (step d). Deprotonation of the alcohol with sodium hydride followed by alkylation with ethyl bromocrotonate should afford the amino alkoxyester (step f). Treatment of this ester using aqueous LiOH solution in a co-solvent should yield the tertiary amino acid (step f).

The keto-phenylvaleric acid of Scheme 3 can be treated with N-methyl-N-propargylamine in the presence of sodium cyanoborohydride under slightly acidic conditions to afford the amino acid (step a). Reduction of the acid can be carried out using lithium aluminum hydride to give the alcohol (step b). The alcohol can be deprotonated with sodium hydride and the resulting alcoholate alkylated with ethyl bromooacetate to provide the ester (step c). Hydrolysis of the ester using aqueous LiOH solution in a co-solvent can give the amino acid (step d). If the alcoholate is alkylated with methyl iodide (step e), the resultant methyl ether can then be treated with butyl lithium followed by ethyl bromoacetate to afford the ester (step f). Hydrolysis of the ester using aqueous LiOH solution in a co-solvent can give the amino acid (step g).

The N-methyl-N-propargyl-4-hydroxybenzyl amine of Scheme 4 can be benzylated with benzyl bromide in the presence of base (step a). The resultant propargyl amine can be deprotonated with n-butyl lithium and then alkylated with ethyl bromocrotonate to afford the aminoester (step b). Hydrolysis of the ester using aqueous LiOH in a co-solvent should afford the amino acid (step c). The benzyloxy group of the tertiary amino ester can then be removed using trifluoroacetic acid (step d).

The N-methyl-N-propargyl-4-hydroxybenzyl amine of Scheme 4 can also be alkylated upon treatment with sodium hyudride and bromochloroethane in the cold (step d). The resultant alkyl halide can then be treated with excess trimethylamine to afford the trimethyl ammonium salt (step e).

Treatment of the N-methyl-N-propargyl-4-hydroxybenzyl amine shown in Scheme 5 with formalin and dimethyl amine followed by further reaction with acetic anhydride and concentrated hydrochloric acid should yield the intermediate chloromethylated phenol. Subsequent reaction with excess trimethyl amine should afford the trimethylammonium salt (step a). Alternatively, the hydroxylbenzyl amine can be alkylated with a substituted benzyl halide such as 3-nitrobenzyl bromide (step b), and the nitro group can be reduced using a reagent such as sodium dithionote to afford the aniline (step c). Reaction of the aniline with methane sulfonyl chloride will afford the sulfonamide (step d).

Tertiary propargyl amines like those shown in Scheme 6 can be treated with an alkyl halide to provide quaternary ammonium salts (step a). Alternatively, tertiary propargyl amines can be treated with hydrogen peroxide to give amine N-oxides (step b).

4-Carboxybenzaldehyde (Scheme 7) can be reductively aminated using N-methyl-N-propargylamine and sodium cyanoborohydride under slightly acidic conditions to provide the tertiary benzyl amine (step a). Treatment of the amino acid with ethyl chloroformate in an appropriate solvent such as methylene chloride in the presence of triethyl amine should give the mixed anhydride and, upon further reaction of with an amino acid ester such as phenylalanine, the ethyl ester should yield the amide (step b). Hydrolysis of the ester using aqueous LiOH in a co-solvent should afford the acid (step c).

As shown in Scheme 8,4-formylcinnamic acid can be reductively aminated using N-methyl-N-propargylamine and sodium cyanoborohydride under slightly acidic conditions to provide the tertiary benzyl amine (step a). Treatment of the amino acid with ethyl chloroformate in an appropriate solvent such as methylene chloride in the presence of triethyl amine should give the mixed anhydride and upon further reaction of with an amino acid ester such as alanine ethyl ester should yield the amide (step b). Hydrolysis of the ester using aqueous LiOH in a co-solvent should afford the acid (step c).

3-(4-Formylphenyl)benzoic acid (Scheme 9) can be reductively aminated using N-methyl-N-propargylamine and sodium cyanoborohydride under slightly acidic conditions to provide the tertiary benzyl amine (step a). Treatment of the amino acid with ethyl chloroformate in an appropriate solvent such as methylene chloride in the presence of triethyl amine should give the mixed anhydride and upon further reaction of with an amino acid ester such as alanine ethyl ester should yield the amide (step b). Hydrolysis of the ester using aqueous LiOH in a co-solvent should afford the acid (step c).

4-(Hydroxy)benzaldehyde of Scheme 10 can be reductively aminated using N-methyl-N-propargylamine and sodium cyanoborohydride under slightly acidic conditions to provide the tertiary benzyl amine (step a). Treatment of the phenol with base, such as sodium hydride, and alkylation with ethyl bromocrotonate should give the amino ester (step b). Hydrolysis of the ester using aqueous LiOH in a co-solvent should afford the acid (step c).

Commercially available 2-formylphenoxyacetic acid can also be reductively aminated using N-methyl-N-propargylamine and sodium cyanoborohydride under slightly acidic conditions to provide the tertiary benzyl amino acid (step d).

In Scheme 11, it is illustrated how the previously described amino alcohol (Scheme 2, step d) can be oxidized to the aldehyde using the Dess-Martin periodinane [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] in wet dichlormethane at about room temperature to give the aldehyde (step a). Treatment of the amino aldehyde with aqueous ammonia or primary amines in the presence of sodium cyanoborohydride under slightly acidic conditions should give the diamino compounds (step b). Reaction of the primary or secondary amines with methane sulfonyl chloride should afford the sulfonamide derivatives (step c). The amines can also be reacted with ethyl 4-bromocrotonate in DMF in the presence of potassium carbonate to give the diaminoester (step d). Subsequent hydrolysis using lithium hydroxide in aqueous THF solution should provide the diamino acid (step e). The amines can also be treated with ethyl malonyl chloride in the presence of pyridine to give the amide ester (step f), which upon subsequent treatment with lithium hydroxide in aqueous THF solution should provide the corresponding acid (step g).

One stereoisomer of a compound of the present invention may be a more potent MAO inhibitor than its counterpart(s). Thus, stereoisomers are included in the present invention. Some of these stereoisomers are shown below in Scheme 12. When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as described in Wilen, S. H. Tables of Resolving Agents and Optical Resolutions 1972, 308 or using enantiomerically pure acids and bases. A chiral compound of the present invention may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen, E. Acc. Chem. Res. 2000, 33, 421-431 or using other enantio- and diastereo-selective reactions and reagents known to one skilled in the art of asymmetric synthesis.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Tables I-VI show representative examples of the compounds of the present invention. Each example in each table represents an individual species of the present invention.

TABLE Ia

Ex. # X¹ X² R¹ 1 H H CO₂Et 2 H H CO₂H 3 H OCH₃ CO₂Et 4 H OCH₃ CO₂H 5 H OCH₂C₆H₅ CO₂Et 6 H OCH₂C₆H₅ CO₂H 7 H OCH₂CH═CH₂ CO₂Et 8 H OCH₂CH═CH₂ CO₂H 9 H N(Et)₂ CO₂Et 10 H N(Et)₂ CO₂H 11 H NO₂ CO₂Et 12 H NO₂ CO₂H 13 H Cl CO₂Et 14 H Cl CO₂H 15 H H CH₂CO₂H 16 H H CH₂CO₂Et 17 H OCH₃ CH₂CO₂H 18 H OCH₃ CH₂CO₂Et 19 H OCH₂C₆H₅ CH₂CO₂H 20 H OCH₂C₆H₅ CH₂CO₂Et 21 H OCH₂CH═CH₂ CH₂CO₂Et 22 H OCH₂CH═CH₂ CH₂CO₂H 23 H N(Et)₂ CH₂CO₂Et 24 H N(Et)₂ CH₂CO₂H 25 H NO₂ CH₂CO₂Et 26 H NO₂ CH₂CO₂H 27 H Cl CH₂CO₂Et 28 H Cl CH₂CO₂H 29 H H CH₂CH═CHCO₂H 30 H H CH₂CH═CHCO₂Et 31 H OCH₃ CH₂CH═CHCO₂H 32 H OCH₃ CH₂CH═CHCO₂Et 33 H OCH₂C₆H₅ CH₂CH═CHCO₂H 34 H OCH₂C₆H₅ CH₂CH═CHCO₂Et 35 H OCH₂CH═CH₂ CH₂CH═CHCO₂H 36 H OCH₂CH═CH₂ CH₂CH═CHCO₂Et 37 H N(Et)₂ CH₂CH═CHCO₂Et 38 H N(Et)₂ CH₂CH═CHCO₂Et 39 H NO₂ CH₂CH═CHCO₂H 40 H NO₂ CH₂CH═CHCO₂Et 41 H Cl CH₂CH═CHCO₂H 42 H Cl CH₂CH═CHCO₂Et 43 H H CH₂PO(OH)₂ 44 H H CH₂PO(OEt)₂ 45 H OCH₃ CH₂PO(OH)₂ 46 H OCH₃ CH₂PO(OEt)₂ 47 H OCH₂C₆H₅ CH₂PO(OH)₂ 48 H OCH₂C₆H₅ CH₂PO(OEt)₂ 49 H OCH₂CH═CH₂ CH₂PO(OH)₂ 50 H OCH₂CH═CH₂ CH₂PO(OEt)₂ 51 H N(Et)₂ CH₂PO(OH)₂ 52 H N(Et)₂ CH₂PO(OEt)₂ 53 H NO₂ CH₂PO(OH)₂ 54 H NO₂ CH₂PO(OEt)₂ 55 H Cl CH₂PO(OH)₂ 56 H Cl CH₂PO(OEt)₂ 57 OCH₃ H CO₂Et 58 OCH₃ H CO₂H 59 OCH₂C₆H₅ H CO₂Et 60 OCH₂C₆H₅ H CO₂H 61 OCH₂CH═CH₂ H CO₂Et 62 OCH₂CH═CH₂ H CO₂H 63 N(Et)₂ H CO₂Et 64 N(Et)₂ H CO₂H 65 NO₂ H CO₂Et 66 NO₂ H CO₂H 67 Cl H CO₂Et 68 Cl H CO₂H 69 OCH₃ H CH₂CO₂H 70 OCH₃ H CH₂CO₂Et 71 OCH₂C₆H₅ H CH₂CO₂H 72 OCH₂C₆H₅ H CH₂CO₂Et 73 OCH₂CH═CH₂ H CH₂CO₂Et 74 OCH₂CH═CH₂ H CH₂CO₂H 75 N(Et)₂ H CH₂CO₂Et 76 N(Et)₂ H CH₂CO₂H 77 NO₂ H CH₂CO₂Et 78 NO₂ H CH₂CO₂H 79 Cl H CH₂CO₂Et 80 Cl H CH₂CO₂H 81 OCH₃ H CH₂CH═CHCO₂H 82 OCH₃ H CH₂CH═CHCO₂Et 83 OCH₂C₆H₅ H CH₂CH═CHCO₂H 84 OCH₂C₆H₅ H CH₂CH═CHCO₂Et 85 OCH₂CH═CH₂ H CH₂CH═CHCO₂H 86 OCH₂CH═CH₂ H CH₂CH═CHCO₂Et 87 OCH₃ H CH₂CH═CHCO₂H 88 OCH₃ H CH₂CH═CHCO₂Et 89 OCH₂C₆H₅ H CH₂CH═CHCO₂H 90 OCH₂C₆H₅ H CH₂CH═CHCO₂Et 91 OCH₂CH═CH₂ H CH₂CH═CHCO₂H 92 OCH₂CH═CH₂ H CH₂CH═CHCO₂Et 93 OCH₃ H CH₂PO(OH)₂ 94 OCH₃ H CH₂PO(OEt)₂ 95 OCH₂C₆H₅ H CH₂PO(OH)₂ 96 OCH₂C₆H₅ H CH₂PO(OEt)₂ 97 OCH₂CH═CH₂ H CH₂PO(OH)₂ 98 OCH₂CH═CH₂ H CH₂PO(OEt)₂ 99 N(Et)₂ H CH₂PO(OH)₂ 100 N(Et)₂ H CH₂PO(OEt)₂ 101 NO₂ H CH₂PO(OH)₂ 102 NO₂ H CH₂PO(OEt)₂ 103 Cl H CH₂PO(OH)₂ 104 Cl H CH₂PO(OEt)₂

TABLE Ib

Ex. # X¹ X² R¹ 1 H H CO₂Et 2 H H CO₂H 3 H OCH₃ CO₂Et 4 H OCH₃ CO₂H 5 H OCH₂C₆H₅ CO₂Et 6 H OCH₂C₆H₅ CO₂H 7 H OCH₂CH═CH₂ CO₂Et 8 H OCH₂CH═CH₂ CO₂H 9 H N(Et)₂ CO₂Et 10 H N(Et)₂ CO₂H 11 H NO₂ CO₂Et 12 H NO₂ CO₂H 13 H Cl CO₂Et 14 H Cl CO₂H 15 H H CH₂CO₂H 16 H H CH₂CO₂Et 17 H OCH₃ CH₂CO₂H 18 H OCH₃ CH₂CO₂Et 19 H OCH₂C₆H₅ CH₂CO₂H 20 H OCH₂C₆H₅ CH₂CO₂Et 21 H OCH₂CH═CH₂ CH₂CO₂Et 22 H OCH₂CH═CH₂ CH₂CO₂H 23 H N(Et)₂ CH₂CO₂Et 24 H N(Et)₂ CH₂CO₂H 25 H NO₂ CH₂CO₂Et 26 H NO₂ CH₂CO₂H 27 H Cl CH₂CO₂Et 28 H Cl CH₂CO₂H 29 H H CH₂CH═CHCO₂H 30 H H CH₂CH═CHCO₂Et 31 H OCH₃ CH₂CH═CHCO₂H 32 H OCH₃ CH₂CH═CHCO₂Et 33 H OCH₂C₆H₅ CH₂CH═CHCO₂H 34 H OCH₂C₆H₅ CH₂CH═CHCO₂Et 35 H OCH₂CH═CH₂ CH₂CH═CHCO₂H 36 H OCH₂CH═CH₂ CH₂CH═CHCO₂Et 37 H N(Et)₂ CH₂CH═CHCO₂H 38 H N(Et)₂ CH₂CH═CHCO₂Et 39 H NO₂ CH₂CH═CHCO₂H 40 H NO₂ CH₂CH═CHCO₂Et 41 H Cl CH₂CH═CHCO₂H 42 H Cl CH₂CH═CHCO₂Et 43 H H CH₂PO(OH)₂ 44 H H CH₂PO(OEt)₂ 45 H OCH₃ CH₂PO(OH)₂ 46 H OCH₃ CH₂PO(OEt)₂ 47 H OCH₂C₆H₅ CH₂PO(OH)₂ 48 H OCH₂C₆H₅ CH₂PO(OEt)₂ 49 H OCH₂CH═CH₂ CH₂PO(OH)₂ 50 H OCH₂CH═CH₂ CH₂PO(OEt)₂ 51 H N(Et)₂ CH₂PO(OH)₂ 52 H N(Et)₂ CH₂PO(OEt)₂ 53 H NO₂ CH₂PO(OH)₂ 54 H NO₂ CH₂PO(OEt)₂ 55 H Cl CH₂PO(OH)₂ 56 H Cl CH₂PO(OEt)₂ 57 OCH₃ H CO₂Et 58 OCH₃ H CO₂H 59 OCH₂C₆H₅ H CO₂Et 60 OCH₂C₆H₅ H CO₂H 61 OCH₂CH═CH₂ H CO₂Et 62 OCH₂CH═CH₂ H CO₂H 63 N(Et)₂ H CO₂Et 64 N(Et)₂ H CO₂H 65 NO₂ H CO₂Et 66 NO₂ H CO₂H 67 Cl H CO₂Et 68 Cl H CO₂H 69 OCH₃ H CH₂CO₂H 70 OCH₃ H CH₂CO₂Et 71 OCH₂C₆H₅ H CH₂CO₂H 72 OCH₂C₆H₅ H CH₂CO₂Et 73 OCH₂CH═CH₂ H CH₂CO₂Et 74 OCH₂CH═CH₂ H CH₂CO₂H 75 N(Et)₂ H CH₂CO₂Et 76 N(Et)₂ H CH₂CO₂H 77 NO₂ H CH₂CO₂Et 78 NO₂ H CH₂CO₂H 79 Cl H CH₂CO₂Et 80 Cl H CH₂CO₂H 81 OCH₃ H CH₂CH═CHCO₂H 82 OCH₃ H CH₂CH═CHCO₂Et 83 OCH₂C₆H₅ H CH₂CH═CHCO₂H 84 OCH₂C₆H₅ H CH₂CH═CHCO₂Et 85 OCH₂CH═CH₂ H CH₂CH═CHCO₂H 86 OCH₂CH═CH₂ H CH₂CH═CHCO₂Et 87 OCH₃ H CH₂CH═CHCO₂H 88 OCH₃ H CH₂CH═CHCO₂Et 89 OCH₂C₆H₅ H CH₂CH═CHCO₂H 90 OCH₂C₆H₅ H CH₂CH═CHCO₂Et 91 OCH₂CH═CH₂ H CH₂CH═CHCO₂H 92 OCH₂CH═CH₂ H CH₂CH═CHCO₂Et 93 OCH₃ H CH₂PO(OH)₂ 94 OCH₃ H CH₂PO(OEt)₂ 95 OCH₂C₆H₅ H CH₂PO(OH)₂ 96 OCH₂C₆H₅ H CH₂PO(OEt)₂ 97 OCH₂CH═CH₂ H CH₂PO(OH)₂ 98 OCH₂CH═CH₂ H CH₂PO(OEt)₂ 99 N(Et)₂ H CH₂PO(OH)₂ 100 N(Et)₂ H CH₂PO(OEt)₂ 101 NO₂ H CH₂PO(OH)₂ 102 NO₂ H CH₂PO(OEt)₂ 103 Cl H CH₂PO(OH)₂ 104 Cl H CH₂PO(OEt)₂

TABLE Ic

Ex. # X¹ X² R¹ 1 H H CO₂Et 2 H H CO₂H 3 H OCH₃ CO₂Et 4 H OCH₃ CO₂H 5 H OCH₂C₆H₅ CO₂Et 6 H OCH₂C₆H₅ CO₂H 7 H OCH₂CH═CH₂ CO₂Et 8 H OCH₂CH═CH₂ CO₂H 9 H N(Et)₂ CO₂Et 10 H N(Et)₂ CO₂H 11 H NO₂ CO₂Et 12 H NO₂ CO₂H 13 H Cl CO₂Et 14 H Cl CO₂H 15 H H CH₂CO₂H 16 H H CH₂CO₂Et 17 H OCH₃ CH₂CO₂H 18 H OCH₃ CH₂CO₂Et 19 H OCH₂C₆H₅ CH₂CO₂H 20 H OCH₂C₆H₅ CH₂CO₂Et 21 H OCH₂CH═CH₂ CH₂CO₂Et 22 H OCH₂CH═CH₂ CH₂CO₂H 23 H N(Et)₂ CH₂CO₂Et 24 H N(Et)₂ CH₂CO₂H 25 H NO₂ CH₂CO₂Et 26 H NO₂ CH₂CO₂H 27 H Cl CH₂CO₂Et 28 H Cl CH₂CO₂H 29 H H CH₂CH═CHCO₂H 30 H H CH₂CH═CHCO₂Et 31 H OCH₃ CH₂CH═CHCO₂H 32 H OCH₃ CH₂CH═CHCO₂Et 33 H OCH₂C₆H₅ CH₂CH═CHCO₂H 34 H OCH₂C₆H₅ CH₂CH═CHCO₂Et 35 H OCH₂CH═CH₂ CH₂CH═CHCO₂H 36 H OCH₂CH═CH₂ CH₂CH═CHCO₂Et 37 H N(Et)₂ CH₂CH═CHCO₂H 38 H N(Et)₂ CH₂CH═CHCO₂Et 39 H NO₂ CH₂CH═CHCO₂H 40 H NO₂ CH₂CH═CHCO₂Et 41 H Cl CH₂CH═CHCO₂H 42 H Cl CH₂CH═CHCO₂Et 43 H H CH₂PO(OH)₂ 44 H H CH₂PO(OEt)₂ 45 H OCH₃ CH₂PO(OH)₂ 46 H OCH₃ CH₂PO(OEt)₂ 47 H OCH₂C₆H₅ CH₂PO(OH)₂ 48 H OCH₂C₆H₅ CH₂PO(OEt)₂ 49 H OCH₂CH═CH₂ CH₂PO(OH)₂ 50 H OCH₂CH═CH₂ CH₂PO(OEt)₂ 51 H N(Et)₂ CH₂PO(OH)₂ 52 H N(Et)₂ CH₂PO(OEt)₂ 53 H NO₂ CH₂PO(OH)₂ 54 H NO₂ CH₂PO(OEt)₂ 55 H Cl CH₂PO(OH)₂ 56 H Cl CH₂PO(OEt)₂ 57 OCH₃ H CO₂Et 58 OCH₃ H CO₂H 59 OCH₂C₆H₅ H CO₂Et 60 OCH₂C₆H₅ H CO₂H 61 OCH₂CH═CH₂ H CO₂Et 62 OCH₂CH═CH₂ H CO₂H 63 N(Et)₂ H CO₂Et 64 N(Et)₂ H CO₂H 65 NO₂ H CO₂Et 66 NO₂ H CO₂H 67 Cl H CO₂Et 68 Cl H CO₂H 69 OCH₃ H CH₂CO₂H 70 OCH₃ H CH₂CO₂Et 71 OCH₂C₆H₅ H CH₂CO₂H 72 OCH₂C₆H₅ H CH₂CO₂Et 73 OCH₂CH═CH₂ H CH₂CO₂Et 74 OCH₂CH═CH₂ H CH₂CO₂H 75 N(Et)₂ H CH₂CO₂Et 76 N(Et)₂ H CH₂CO₂H 77 NO₂ H CH₂CO₂Et 78 NO₂ H CH₂CO₂H 79 Cl H CH₂CO₂Et 80 Cl H CH₂CO₂H 81 OCH₃ H CH₂CH═CHCO₂H 82 OCH₃ H CH₂CH═CHCO₂Et 83 OCH₂C₆H₅ H CH₂CH═CHCO₂H 84 OCH₂C₆H₅ H CH₂CH═CHCO₂Et 85 OCH₂CH═CH₂ H CH₂CH═CHCO₂H 86 OCH₂CH═CH₂ H CH₂CH═CHCO₂Et 87 OCH₃ H CH₂CH═CHCO₂H 88 OCH₃ H CH₂CH═CHCO₂Et 89 OCH₂C₆H₅ H CH₂CH═CHCO₂H 90 OCH₂C₆H₅ H CH₂CH═CHCO₂Et 91 OCH₂CH═CH₂ H CH₂CH═CHCO₂H 92 OCH₂CH═CH₂ H CH₂CH═CHCO₂Et 93 OCH₃ H CH₂PO(OH)₂ 94 OCH₃ H CH₂PO(OEt)₂ 95 OCH₂C₆H₅ H CH₂PO(OH)₂ 96 OCH₂C₆H₅ H CH₂PO(OEt)₂ 97 OCH₂CH═CH₂ H CH₂PO(OH)₂ 98 OCH₂CH═CH₂ H CH₂PO(OEt)₂ 99 N(Et)₂ H CH₂PO(OH)₂ 100 N(Et)₂ H CH₂PO(OEt)₂ 101 NO₂ H CH₂PO(OH)₂ 102 NO₂ H CH₂PO(OEt)₂ 103 Cl H CH₂PO(OH)₂ 104 Cl H CH₂PO(OEt)₂

TABLE Id

Ex. # X¹ X² R¹ 1 H H CO₂Et 2 H H CO₂H 3 H OCH₃ CO₂Et 4 H OCH₃ CO₂H 5 H OCH₂C₆H₅ CO₂Et 6 H OCH₂C₆H₅ CO₂H 7 H OCH₂CH═CH₂ CO₂Et 8 H OCH₂CH═CH₂ CO₂H 9 H N(Et)₂ CO₂Et 10 H N(Et)₂ CO₂H 11 H NO₂ CO₂Et 12 H NO₂ CO₂H 13 H Cl CO₂Et 14 H Cl CO₂H 15 H H CH₂CO₂H 16 H H CH₂CO₂Et 17 H OCH₃ CH₂CO₂H 18 H OCH₃ CH₂CO₂Et 19 H OCH₂C₆H₅ CH₂CO₂H 20 H OCH₂C₆H₅ CH₂CO₂Et 21 H OCH₂CH═CH₂ CH₂CO₂Et 22 H OCH₂CH═CH₂ CH₂CO₂H 23 H N(Et)₂ CH₂CO₂Et 24 H N(Et)₂ CH₂CO₂H 25 H NO₂ CH₂CO₂Et 26 H NO₂ CH₂CO₂H 27 H Cl CH₂CO₂Et 28 H Cl CH₂CO₂H 29 H H CH₂CH═CHCO₂H 30 H H CH₂CH═CHCO₂Et 31 H OCH₃ CH₂CH═CHCO₂H 32 H OCH₃ CH₂CH═CHCO₂Et 33 H OCH₂C₆H₅ CH₂CH═CHCO₂H 34 H OCH₂C₆H₅ CH₂CH═CHCO₂Et 35 H OCH₂CH═CH₂ CH₂CH═CHCO₂H 36 H OCH₂CH═CH₂ CH₂CH═CHCO₂Et 37 H N(Et)₂ CH₂CH═CHCO₂H 38 H N(Et)₂ CH₂CH═CHCO₂Et 39 H NO₂ CH₂CH═CHCO₂H 40 H NO₂ CH₂CH═CHCO₂Et 41 H Cl CH₂CH═CHCO₂H 42 H Cl CH₂CH═CHCO₂Et 43 H H CH₂PO(OH)₂ 44 H H CH₂PO(OEt)₂ 45 H OCH₃ CH₂PO(OH)₂ 46 H OCH₃ CH₂PO(OEt)₂ 47 H OCH₂C₆H₅ CH₂PO(OH)₂ 48 H OCH₂C₆H₅ CH₂PO(OEt)₂ 49 H OCH₂CH═CH₂ CH₂PO(OH)₂ 50 H OCH₂CH═CH₂ CH₂PO(OEt)₂ 51 H N(Et)₂ CH₂PO(OH)₂ 52 H N(Et)₂ CH₂PO(OEt)₂ 53 H NO₂ CH₂PO(OH)₂ 54 H NO₂ CH₂PO(OEt)₂ 55 H Cl CH₂PO(OH)₂ 56 H Cl CH₂PO(OEt)₂ 57 OCH₃ H CO₂Et 58 OCH₃ H CO₂H 59 OCH₂C₆H₅ H CO₂Et 60 OCH₂C₆H₅ H CO₂H 61 OCH₂CH═CH₂ H CO₂Et 62 OCH₂CH═CH₂ H CO₂H 63 N(Et)₂ H CO₂Et 64 N(Et)₂ H CO₂H 65 NO₂ H CO₂Et 66 NO₂ H CO₂H 67 Cl H CO₂Et 68 Cl H CO₂H 69 OCH₃ H CH₂CO₂H 70 OCH₃ H CH₂CO₂Et 71 OCH₂C₆H₅ H CH₂CO₂H 72 OCH₂C₆H₅ H CH₂CO₂Et 73 OCH₂CH═CH₂ H CH₂CO₂Et 74 OCH₂CH═CH₂ H CH₂CO₂H 75 N(Et)₂ H CH₂CO₂Et 76 N(Et)₂ H CH₂CO₂H 77 NO₂ H CH₂CO₂Et 78 NO₂ H CH₂CO₂H 79 Cl H CH₂CO₂Et 80 Cl H CH₂CO₂H 81 OCH₃ H CH₂CH═CHCO₂H 82 OCH₃ H CH₂CH═CHCO₂Et 83 OCH₂C₆H₅ H CH₂CH═CHCO₂H 84 OCH₂C₆H₅ H CH₂CH═CHCO₂Et 85 OCH₂CH═CH₂ H CH₂CH═CHCO₂H 86 OCH₂CH═CH₂ H CH₂CH═COCO₂Et 87 OCH₃ H CH₂CH═CHCO₂H 88 OCH₃ H CH₂CH═CHCO₂Et 89 OCH₂C₆H₅ H CH₂CH═CHCO₂H 90 OCH₂C₆H₅ H CH₂CH═CHCO₂Et 91 OCH₂CH═CH₂ H CH₂CH═CHCO₂H 92 OCH₂CH═CH₂ H CH₂CH═CHCO₂Et 93 OCH₃ H CH₂PO(OH)₂ 94 OCH₃ H CH₂PO(OEt)₂ 95 OCH₂C₆H₅ H CH₂PO(OH)₂ 96 OCH₂C₆H₅ H CH₂PO(OEt)₂ 97 OCH₂CH═CH₂ H CH₂PO(OH)₂ 98 OCH₂CH═CH₂ H CH₂PO(OEt)₂ 99 N(Et)₂ H CH₂PO(OH)₂ 100 N(Et)₂ H CH₂PO(OEt)₂ 101 NO₂ H CH₂PO(OH)₂ 102 NO₂ H CH₂PO(OEt)₂ 103 Cl H CH₂PO(OH)₂ 104 Cl H CH₂PO(OEt)₂

TABLE IIa

Ex. # X¹ Q 1 H CO₂Et 2 H CO₂H 3 OCH₃ CO₂Et 4 OCH₃ CO₂H 5 OCH₂C₆H₅ CO₂Et 6 OCH₂C₆H₅ CO₂H 7 OCH₂CH═CH₂ CO₂Et 8 OCH₂CH═CH₂ CO₂H 9 N(Et)₂ CO₂Et 10 N(Et)₂ CO₂H 11 NO₂ CO₂Et 12 NO₂ CO₂H 13 Cl CO₂Et 14 Cl CO₂H 15 H CH₂CO₂Et 16 H CH₂CO₂H 17 OCH₃ CH₂CO₂Et 18 OCH₃ CH₂CO₂H 19 OCH₂C₆H₅ CH₂CO₂Et 20 OCH₂C₆H₅ CH₂CO₂H 21 OCH₂CH═CH₂ CH₂CO₂Et 22 OCH₂CH═CH₂ CH₂CO₂H 23 N(Et)₂ CH₂CO₂Et 24 N(Et)₂ CH₂CO₂H 25 NO₂ CH₂CO₂Et 26 NO₂ CH₂CO₂H 27 Cl CH₂CO₂Et 28 Cl CH₂CO₂H 29 H CH₂OCH₂CH═CHCO₂Et 30 H CH₂OCH₂CH═CHCO₂H 31 OCH₃ CH₂OCH₂CH═CHCO₂Et 32 OCH₃ CH₂OCH₂CH═CHCO₂H 33 OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂Et 34 OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂H 35 OCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂Et 36 OCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂H 37 N(Et)₂ CH₂OCH₂CH═CHCO₂Et 38 N(Et)₂ CH₂OCH₂CH═CHCO₂H 39 NO₂ CH₂OCH₂CH═CHCO₂Et 40 NO₂ CH₂OCH₂CH═CHCO₂H 41 Cl CH₂OCH₂CH═CHCO₂Et 42 Cl CH₂OCH₂CH═CHCO₂H 43 H CH₂OCH₂CO₂Et 44 H CH₂OCH₂CO₂H 45 OCH₃ CH₂OCH₂CO₂Et 46 OCH₃ CH₂OCH₂CO₂H 47 OCH₂C₆H₅ CH₂OCH₂CO₂Et 48 OCH₂C₆H₅ CH₂OCH₂CO₂H 49 OCH₂CH═CH₂ CH₂OCH₂CO₂Et 50 OCH₂CH═CH₂ CH₂OCH₂CO₂H 51 N(Et)₂ CH₂OCH₂CO₂Et 52 N(Et)₂ CH₂OCH₂CO₂H 53 NO₂ CH₂OCH₂CO₂Et 54 NO₂ CH₂OCH₂CO₂H 55 Cl CH₂OCH₂CO₂Et 56 Cl CH₂OCH₂CO₂H 57 H CH₂OCH₂PO(OEt)₂ 58 H CH₂OCH₂PO(OH)₂ 59 OCH₃ CH₂OCH₂PO(OEt)₂ 60 OCH₃ CH₂OCH₂PO(OH)₂ 61 OCH₂C₆H₅ CH₂OCH₂PO(OEt)₂ 62 OCH₂C₆H₅ CH₂OCH₂PO(OH)₂ 63 OCH₂CH═CH₂ CH₂OCH₂PO(OEt)₂ 64 OCH₂CH═CH₂ CH₂OCH₂PO(OH)₂ 65 N(Et)₂ CH₂OCH₂PO(OEt)₂ 66 N(Et)₂ CH₂OCH₂PO(OH)₂ 67 NO₂ CH₂OCH₂PO(OEt)₂ 68 NO₂ CH₂OCH₂PO(OH)₂ 69 Cl CH₂OCH₂PO(OEt)₂ 70 Cl CH₂OCH₂PO(OH)₂ 71 H CH₂CH₂CH₂CO₂Et 72 H CH₂CH₂CH₂CO₂H 73 OCH₃ CH₂CH₂CH₂CO₂Et 74 OCH₃ CH₂CH₂CH₂CO₂H 75 OCH₂C₆H₅ CH₂CH₂CH₂CO₂Et 76 OCH₂C₆H₅ CH₂CH₂CH₂CO₂H 77 OCH₂CH═CH₂ CH₂CH₂CH₂CO₂Et 78 OCH₂CH═CH₂ CH₂CH₂CH₂CO₂H 79 N(Et)₂ CH₂CH₂CH₂CO₂Et 80 N(Et)₂ CH₂CH₂CH₂CO₂H 81 NO₂ CH₂CH₂CH₂CO₂Et 82 NO₂ CH₂CH₂CH₂CO₂H 83 Cl CH₂CH₂CH₂CO₂Et 84 Cl CH₂CH₂CH₂CO₂H 85 H CH₂CH₂OCH₂CO₂Et 86 H CH₂CH₂OCH₂CO₂H 87 OCH₃ CH₂CH₂OCH₂CO₂Et 88 OCH₃ CH₂CH₂OCH₂CO₂H 89 OCH₂C₆H₅ CH₂CH₂OCH₂CO₂Et 90 OCH₂C₆H₅ CH₂CH₂OCH₂CO₂H 91 OCH₂CH═CH₂ CH₂CH₂OCH₂CO₂Et 92 OCH₂CH═CH₂ CH₂CH₂OCH₂CO₂H 93 N(Et)₂ CH₂CH₂OCH₂CO₂Et 94 N(Et)₂ CH₂CH₂OCH₂CO₂H 95 NO₂ CH₂CH₂OCH₂CO₂Et 96 NO₂ CH₂CH₂OCH₂CO₂H 97 Cl CH₂CH₂OCH₂CO₂Et 98 Cl CH₂CH₂OCH₂CO₂H 99 H CH₂CH₂OCH₂PO(OEt)₂ 100 H CH₂CH₂OCH₂PO(OH)₂ 101 OCH₃ CH₂CH₂OCH₂PO(OEt)₂ 102 OCH₃ CH₂CH₂OCH₂PO(OH)₂ 103 OCH₂C₆H₅ CH₂CH₂OCH₂PO(OEt)₂ 104 OCH₂C₆H₅ CH₂CH₂OCH₂PO(OH)₂ 105 OCH₂CH═CH₂ CH₂CH₂OCH₂PO(OEt)₂ 106 OCH₂CH═CH₂ CH₂CH₂OCH₂PO(OH)₂ 107 N(Et)₂ CH₂CH₂OCH₂PO(OEt)₂ 108 N(Et)₂ CH₂CH₂OCH₂PO(OH)₂ 109 NO₂ CH₂CH₂OCH₂PO(OEt)₂ 110 NO₂ CH₂CH₂OCH₂PO(OH)₂ 111 Cl CH₂CH₂OCH₂PO(OEt)₂ 112 Cl CH₂CH₂OCH₂PO(OH)₂ 113 H CH₂CH₂CH₂CH₂OCH₂CO₂Et 114 H CH₂CH₂CH₂CH₂OCH₂CO₂H 115 OCH₃ CH₂CH₂CH₂CH₂OCH₂CO₂Et 116 OCH₃ CH₂CH₂CH₂CH₂OCH₂CO₂H 117 OCH₂C₆H₅ CH₂CH₂CH₂CH₂OCH₂CO₂Et 118 OCH₂C₆H₅ CH₂CH₂CH₂CH₂OCH₂CO₂H 119 OCH₂CH═CH₂ CH₂CH₂CH₂CH₂OCH₂CO₂Et 120 OCH₂CH═CH₂ CH₂CH₂CH₂CH₂OCH₂CO₂H 121 N(Et)₂ CH₂CH₂CH₂CH₂OCH₂CO₂Et 122 N(Et)₂ CH₂CH₂CH₂CH₂OCH₂CO₂H 123 NO₂ CH₂CH₂CH₂CH₂OCH₂CO₂Et 124 NO₂ CH₂CH₂CH₂CH₂OCH₂CO₂H 125 Cl CH₂CH₂CH₂CH₂OCH₂CO₂Et 126 Cl CH₂CH₂CH₂CH₂OCH₂CO₂H 127 H CH₂NHCH₂PO(OEt)₂ 128 H CH₂NHCH₂PO(OH)₂ 129 OCH₃ CH₂NHCH₂PO(OEt)₂ 130 OCH₃ CH₂NHCH₂PO(OH)₂ 131 OCH₂C₆H₅ CH₂NHCH₂PO(OEt)₂ 132 OCH₂C₆H₅ CH₂NHCH₂PO(OH)₂ 133 OCH₂CH═CH₂ CH₂NHCH₂PO(OEt)₂ 134 OCH₂CH═CH₂ CH₂NHCH₂PO(OH)₂ 135 N(Et)₂ CH₂NHCH₂PO(OEt)₂ 136 N(Et)₂ CH₂NHCH₂PO(OH)₂ 137 NO₂ CH₂NHCH₂PO(OEt)₂ 138 NO₂ CH₂NHCH₂PO(OH)₂ 139 Cl CH₂NHCH₂PO(OEt)₂ 140 Cl CH₂NHCH₂PO(OH)₂ 141 H CH₂NHCH₂CO₂Et 142 H CH₂NHCH₂CO₂H 143 OCH₃ CH₂NHCH₂CO₂Et 144 OCH₃ CH₂NHCH₂CO₂H 145 OCH₂C₆H₅ CH₂NHCH₂CO₂Et 146 OCH₂C₆H₅ CH₂NHCH₂CO₂H 147 OCH₂CH═CH₂ CH₂NHCH₂CO₂Et 148 OCH₂CH═CH₂ CH₂NHCH₂CO₂H 149 N(Et)₂ CH₂NHCH₂CO₂Et 150 N(Et)₂ CH₂NHCH₂CO₂H 151 NO₂ CH₂NHCH₂CO₂Et 152 NO₂ CH₂NHCH₂CO₂H 153 Cl CH₂NHCH₂CO₂Et 154 Cl CH₂NHCH₂CO₂H 155 H CH₂NHCH₂CH═CHCO₂Et 156 H CH₂NHCH₂CH═CHCO₂H 157 OCH₃ HC₂NHCH₂CH═CHCO₂Et 158 OCH₃ CH₂NHCH₂CH═CHCO₂H 159 OCH₂C₆H₅ CH₂NHCH₂CH═CHCO₂Et 160 OCH₂C₆H₅ CH₂NHCH₂CH═CHCO₂H 161 OCH₂CH═CH₂ CH₂NHCH₂CH═CHCO₂Et 162 OCH₂CH═CH₂ CH₂NHCH₂CH═CHCO₂H 163 N(Et)₂ CH₂NHCH₂CH═CHCO₂Et 164 N(Et)₂ CH₂NHCH₂CH═CHCO₂H 165 NO₂ CH₂NHCH₂CH═CHCO₂Et 166 NO₂ CH₂NHCH₂CH═CHCO₂H 167 Cl CH₂NHCH₂CH═CHCO₂Et 168 Cl CH₂NHCH₂CH═CHCO₂H

TABLE IIb

Ex. # X¹ Q 1 H CO₂Et 2 H CO₂H 3 OCH₃ CO₂Et 4 OCH₃ CO₂H 5 OCH₂C₆H₅ CO₂Et 6 OCH₂C₆H₅ CO₂H 7 OCH₂CH═CH₂ CO₂Et 8 OCH₂CH═CH₂ CO₂H 9 N(Et)₂ CO₂Et 10 N(Et)₂ CO₂H 11 NO₂ CO₂Et 12 NO₂ CO₂H 13 Cl CO₂Et 14 Cl CO₂H 15 H CH₂CO₂Et 16 H CH₂CO₂H 17 OCH₃ CH₂CO₂Et 18 OCH₃ CH₂CO₂H 19 OCH₂C₆H₅ CH₂CO₂Et 20 OCH₂C₆H₅ CH₂CO₂H 21 OCH₂CH═CH₂ CH₂CO₂Et 22 OCH₂CH═CH₂ CH₂CO₂H 23 N(Et)₂ CH₂CO₂Et 24 N(Et)₂ CH₂CO₂H 25 NO₂ CH₂CO₂Et 26 NO₂ CH₂CO₂H 27 Cl CH₂CO₂Et 28 Cl CH₂CO₂H 29 H CH₂OCH₂CH═CHCO₂Et 30 H CH₂OCH₂CH═CHCO₂H 31 OCH₃ CH₂OCH₂CH═CHCO₂Et 32 OCH₃ CH₂OCH₂CH═CHCO₂H 33 OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂Et 34 OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂H 35 OCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂Et 36 OCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂H 37 N(Et)₂ CH₂OCH₂CH═CHCO₂Et 38 N(Et)₂ CH₂OCH₂CH═CHCO₂H 39 NO₂ CH₂OCH₂CH═CHCO₂Et 40 NO₂ CH₂OCH₂CH═CHCO₂H 41 Cl CH₂OCH₂CH═CHCO₂Et 42 Cl CH₂OCH₂CH═CHCO₂H 43 H CH₂OCH₂CO₂Et 44 H CH₂OCH₂CO₂H 45 OCH₃ CH₂OCH₂CO₂Et 46 OCH₃ CH₂OCH₂CO₂H 47 OCH₂C₆H₅ CH₂OCH₂CO₂Et 48 OCH₂C₆H₅ CH₂OCH₂CO₂H 49 OCH₂CH═CH₂ CH₂OCH₂CO₂Et 50 OCH₂CH═CH₂ CH₂OCH₂CO₂H 51 N(Et)₂ CH₂OCH₂CO₂Et 52 N(Et)₂ CH₂OCH₂CO₂H 53 NO₂ CH₂OCH₂CO₂Et 54 NO₂ CH₂OCH₂CO₂H 55 Cl CH₂OCH₂CO₂Et 56 Cl CH₂OCH₂CO₂H 57 H CH₂OCH₂PO(OEt)₂ 58 H CH₂OCH₂PO(OH)₂ 59 OCH₃ CH₂OCH₂PO(OEt)₂ 60 OCH₃ CH₂OCH₂PO(OH)₂ 61 OCH₂C₆H₅ CH₂OCH₂PO(OEt)₂ 62 OCH₂C₆H₅ CH₂OCH₂PO(OH)₂ 63 OCH₂CH═CH₂ CH₂OCH₂PO(OEt)₂ 64 OCH₂CH═CH₂ CH₂OCH₂PO(OH)₂ 65 N(Et)₂ CH₂OCH₂PO(OEt)₂ 66 N(Et)₂ CH₂OCH₂PO(OH)₂ 67 NO₂ CH₂OCH₂PO(OEt)₂ 68 NO₂ CH₂OCH₂PO(OH)₂ 69 Cl CH₂OCH₂PO(OEt)₂ 70 Cl CH₂OCH₂PO(OH)₂ 71 H CH₂CH₂CH₂CO₂Et 72 H CH₂CH₂CH₂CO₂H 73 OCH₃ CH₂CH₂CH₂CO₂Et 74 OCH₃ CH₂CH₂CH₂CO₂H 75 OCH₂C₆H₅ CH₂CH₂CH₂CO₂Et 76 OCH₂C₆H₅ CH₂CH₂CH₂CO₂H 77 OCH₂CH═CH₂ CH₂CH₂CH₂CO₂Et 78 OCH₂CH═CH₂ CH₂CH₂CH₂CO₂H 79 N(Et)₂ CH₂CH₂CH₂CO₂Et 80 N(Et)₂ CH₂CH₂CH₂CO₂H 81 NO₂ CH₂CH₂CH₂CO₂Et 82 NO₂ CH₂CH₂CH₂CO₂H 83 Cl CH₂CH₂CH₂CO₂Et 84 Cl CH₂CH₂CH₂CO₂H 85 H CH₂CH₂OCH₂CO₂Et 86 H CH₂CH₂OCH₂CO₂H 87 OCH₃ CH₂CH₂OCH₂CO₂Et 88 OCH₃ CH₂CH₂OCH₂CO₂H 89 OCH₂C₆H₅ CH₂CH₂OCH₂CO₂Et 90 OCH₂C₆H₅ CH₂CH₂OCH₂CO₂H 91 OCH₂CH═CH₂ CH₂CH₂OCH₂CO₂Et 92 OCH₂CH═CH₂ CH₂CH₂OCH₂CO₂H 93 N(Et)₂ CH₂CH₂OCH₂CO₂Et 94 N(Et)₂ CH₂CH₂OCH₂CO₂H 95 NO₂ CH₂CH₂OCH₂CO₂Et 96 NO₂ CH₂CH₂OCH₂CO₂H 97 Cl CH₂CH₂OCH₂CO₂Et 98 Cl CH₂CH₂OCH₂CO₂H 99 H CH₂CH₂OCH₂PO(OEt)₂ 100 H CH₂CH₂OCH₂PO(OH)₂ 101 OCH₃ CH₂CH₂OCH₂PO(OEt)₂ 102 OCH₃ CH₂CH₂OCH₂PO(OH)₂ 103 OCH₂C₆H₅ CH₂CH₂OCH₂PO(OEt)₂ 104 OCH₂C₆H₅ CH₂CH₂OCH₂PO(OH)₂ 105 OCH₂CH═CH₂ CH₂CH₂OCH₂PO(OEt)₂ 106 OCH₂CH═CH₂ CH₂CH₂OCH₂PO(OH)₂ 107 N(Et)₂ CH₂CH₂OCH₂PO(OEt)₂ 108 N(Et)₂ CH₂CH₂OCH₂PO(OH)₂ 109 NO₂ CH₂CH₂OCH₂PO(OEt)₂ 110 NO₂ CH₂CH₂OCH₂PO(OH)₂ 111 Cl CH₂CH₂OCH₂PO(OEt)₂ 112 Cl CH₂CH₂OCH₂PO(OH)₂ 113 H CH₂CH₂CH₂CH₂OCH₂CO₂Et 114 H CH₂CH₂CH₂CH₂OCH₂CO₂H 115 OCH₃ CH₂CH₂CH₂CH₂OCH₂CO₂Et 116 OCH₃ CH₂CH₂CH₂CH₂OCH₂CO₂H 117 OCH₂C₆H₅ CH₂CH₂CH₂CH₂OCH₂CO₂Et 118 OCH₂C₆H₅ CH₂CH₂CH₂CH₂OCH₂CO₂H 119 OCH₂CH═CH₂ CH₂CH₂CH₂CH₂OCH₂CO₂Et 120 OCH₂CH═CH₂ CH₂CH₂CH₂CH₂OCH₂CO₂H 121 N(Et)₂ CH₂CH₂CH₂CH₂OCH₂CO₂Et 122 N(Et)₂ CH₂CH₂CH₂CH₂OCH₂CO₂H 123 NO₂ CH₂CH₂CH₂CH₂OCH₂CO₂Et 124 NO₂ CH₂CH₂CH₂CH₂OCH₂CO₂H 125 Cl CH₂CH₂CH₂CH₂OCH₂CO₂Et 126 Cl CH₂CH₂CH₂CH₂OCH₂CO₂H 127 H CH₂NHCH₂PO(OEt)₂ 128 H CH₂NHCH₂PO(OH)₂ 129 OCH₃ CH₂NHCH₂PO(OEt)₂ 130 OCH₃ CH₂NHCH₂PO(OH)₂ 131 OCH₂C₆H₅ CH₂NHCH₂PO(OEt)₂ 132 OCH₂C₆H₅ CH₂NHCH₂PO(OH)₂ 133 OCH₂CH═CH₂ CH₂NHCH₂PO(OEt)₂ 134 OCH₂CH═CH₂ CH₂NHCH₂PO(OH)₂ 135 N(Et)₂ CH₂NHCH₂PO(OEt)₂ 136 N(Et)₂ CH₂NHCH₂PO(OH)₂ 137 NO₂ CH₂NHCH₂PO(OEt)₂ 138 NO₂ CH₂NHCH₂PO(OH)₂ 139 Cl CH₂NHCH₂PO(OEt)₂ 140 Cl CH₂NHCH₂PO(OH)₂ 141 H CH₂NHCH₂CO₂Et 142 H CH₂NHCH₂CO₂H 143 OCH₃ CH₂NHCH₂CO₂Et 144 OCH₃ CH₂NHCH₂CO₂H 145 OCH₂C₆H₅ CH₂NHCH₂CO₂Et 146 OCH₂C₆H₅ CH₂NHCH₂CO₂H 147 OCH₂CH═CH₂ CH₂NHCH₂CO₂Et 148 OCH₂CH═CH₂ CH₂NHCH₂CO₂H 149 N(Et)₂ CH₂NHCH₂CO₂Et 150 N(Et)₂ CH₂NHCH₂CO₂H 151 NO₂ CH₂NHCH₂CO₂Et 152 NO₂ CH₂NHCH₂CO₂H 153 Cl CH₂NHCH₂CO₂Et 154 Cl CH₂NHCH₂CO₂H 155 H CH₂NHCH₂CH═CHCO₂Et 156 H CH₂NHCH₂CH═CHCO₂H 157 OCH₃ CH₂NHCH₂CH═CHCO₂Et 158 OCH₃ CH₂NHCH₂CH═CHCO₂H 159 OCH₂C₆H₅ CH₂NHCH₂CH═CHCO₂Et 160 OCH₂C₆H₅ CH₂NHCH₂CH═CHCO₂H 161 OCH₂CH═CH₂ CH₂NHCH₂CH═CHCO₂Et 162 OCH₂CH═CH₂ CH₂NHCH₂CH═CHCO₂H 163 N(Et)₂ CH₂NHCH₂CH═CHCO₂Et 164 N(Et)₂ CH₂NHCH₂CH═CHCO₂H 165 NO₂ CH₂NHCH₂CH═CHCO₂Et 166 NO₂ CH₂NHCH₂CH═CHCO₂H 167 Cl CH₂NHCH₂CH═CHCO₂Et 168 Cl CH₂NHCH₂CH═CHCO₂H

TABLE IIIa

Ex. # Q X 1 H CO₂Et 2 H CO₂H 3 CH₂OCH₃ CO₂Et 4 CH₂OCH₃ CO₂H 5 CH₂OCH₂C₆H₅ CO₂Et 6 CH₂OCH₂C₆H₅ CO₂H 7 CH₂OCH₂CH═CH₂ CO₂Et 8 CH₂OCH₂CH═CH₂ CO₂H 9 CH₂CH₂CH₂CH₂OCH₃ CO₂Et 10 CH₂CH₂CH₂CH₂OCH₃ CO₂H 11 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CO₂Et 12 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CO₂H 13 CH₃ CO₂Et 14 CH₃ CO₂H 15 H CH₂CO₂Et 16 H CH₂CO₂H 17 CH₂OCH₃ CH₂CO₂Et 18 CH₂OCH₃ CH₂CO₂H 19 CH₂OCH₂C₆H₅ CH₂CO₂Et 20 CH₂OCH₂C₆H₅ CH₂CO₂H 21 CH₂OCH₂CH═CH₂ CH₂CO₂Et 22 CH₂OCH₂CH═CH₂ CH₂CO₂H 23 CH₂CH₂CH₂CH₂OCH₃ CH₂CO₂Et 24 CH₂CH₂CH₂CH₂OCH₃ CH₂CO₂H 25 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂CO₂Et 26 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂CO₂H 27 CH₃ CH₂CO₂Et 28 CH₃ CH₂CO₂H 29 H CH₂OCH₂CH═CHCO₂Et 30 H CH₂OCH₂CH═CHCO₂H 31 CH₂OCH₃ CH₂OCH₂CH═CHCO₂Et 32 CH₂OCH₃ CH₂OCH₂CH═CHCO₂H 33 CH₂OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂Et 34 CH₂OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂H 35 CH₂OCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂Et 36 CH₂OCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂H 37 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂CH═CHCO₂Et 38 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂CH═CHCO₂H 39 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂Et 40 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂H 41 CH₃ CH₂OCH₂CH═CHCO₂Et 42 CH₃ CH₂OCH₂CH═CHCO₂H 43 H CH₂OCH₂CO₂Et 44 H CH₂OCH₂CO₂H 45 CH₂OCH₃ CH₂OCH₂CO₂Et 46 CH₂OCH₃ CH₂OCH₂CO₂H 47 CH₂OCH₂C₆H₅ CH₂OCH₂CO₂Et 48 CH₂OCH₂C₆H₅ CH₂OCH₂CO₂H 49 CH₂OCH₂CH═CH₂ CH₂OCH₂CO₂Et 50 CH₂OCH₂CH═CH₂ CH₂OCH₂CO₂H 51 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂CO₂Et 52 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂CO₂H 53 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂CO₂Et 54 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂CO₂H 55 CH₃ CH₂OCH₂CO₂Et 56 CH₃ CH₂OCH₂CO₂H 57 H CH₂OCH₂PO(OEt)₂ 58 H CH₂OCH₂PO(OH)₂ 59 CH₂OCH₃ CH₂OCH₂PO(OEt)₂ 60 CH₂OCH₃ CH₂OCH₂PO(OH)₂ 61 CH₂OCH₂C₆H₅ CH₂OCH₂PO(OEt)₂ 62 CH₂OCH₂C₆H₅ CH₂OCH₂PO(OH)₂ 63 CH₂OCH₂CH═CH₂ CH₂OCH₂PO(OEt)₂ 64 CH₂OCH₂CH═CH₂ CH₂OCH₂PO(OH)₂ 65 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂PO(OEt)₂ 66 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂PO(OH)₂ 67 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂PO(OEt)₂ 68 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂PO(OH)₂ 69 CH₃ CH₂OCH₂PO(OEt)₂ 70 CH₃ CH₂OCH₂PO(OH)₂ 71 H CH═CHCO₂Et 72 H CH═CHCO₂H 73 CH₂OCH₃ CH═CHCO₂Et 74 CH₂OCH₃ CH═CHCO₂H 75 CH₂OCH₂C₆H₅ CH═CHCO₂Et 76 CH₂OCH₂C₆H₅ CH═CHCO₂H 77 CH₂OCH₂CH═CH₂ CH═CHCO₂Et 78 CH₂OCH₂CH═CH₂ CH═CHCO₂H 79 CH₂CH₂CH₂CH₂OCH₃ CH═CHCO₂Et 80 CH₂CH₂CH₂CH₂OCH₃ CH═CHCO₂H 81 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH═CHCO₂Et 82 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH═CHCO₂H 83 CH₃ CH═CHCO₂Et 84 CH₃ CH═CHCO₂H 85 H C₆H₄CO₂Et 86 H C₆H₄CO₂H 87 CH₂OCH₃ C₆H₄CO₂Et 88 CH₂OCH₃ C₆H₄CO₂H 89 CH₂OCH₂C₆H₅ C₆H₄CO₂Et 90 CH₂OCH₂C₆H₅ C₆H₄CO₂H 91 CH₂OCH₂CH═CH₂ C₆H₄CO₂Et 92 CH₂OCH₂CH═CH₂ C₆H₄CO₂H 93 CH₂CH₂CH₂CH₂OCH₃ C₆H₄CO₂Et 94 CH₂CH₂CH₂CH₂OCH₃ C₆H₄CO₂H 95 CH₂CH₂CH₂CH₂OCH₂C₆H₅ C₆H₄CO₂Et 96 CH₂CH₂CH₂CH₂OCH₂C₆H₅ C₆H₄CO₂H 97 CH₃ C₆H₄CO₂Et 98 CH₃ C₆H₄CO₂H 99 H OCH₂PO(OEt)₂ 100 H OCH₂PO(OH)₂ 101 CH₂OCH₃ OCH₂PO(OEt)₂ 102 CH₂OCH₃ OCH₂PO(OH)₂ 103 CH₂OCH₂C₆H₅ OCH₂PO(OEt)₂ 104 CH₂OCH₂C₆H₅ OCH₂PO(OH)₂ 105 CH₂OCH₂CH═CH₂ OCH₂PO(OEt)₂ 106 CH₂OCH₂CH═CH₂ OCH₂PO(OH)₂ 107 CH₂CH₂CH₂CH₂OCH₃ OCH₂PO(OEt)₂ 108 CH₂CH₂CH₂CH₂OCH₃ OCH₂PO(OH)₂ 109 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂PO(OEt)₂ 110 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂PO(OH)₂ 111 CH₃ OCH₂PO(OEt)₂ 112 CH₃ OCH₂PO(OH)₂ 113 H CH═CHCONHCH(CH₃)CO₂Et 114 H CH═CHCONHCH(CH₃)CO₂H 115 CH₂OCH₃ CH═CHCONHCH(CH₃)CO₂Et 116 CH₂OCH₃ CH═CHCONHCH(CH₃)CO₂H 117 CH₂OCH₂C₆H₅ CH═CHCONHCH(CH₃)CO₂Et 118 CH₂OCH₂C₆H₅ CH═CHCONHCH(CH₃)CO₂H 119 CH₂OCH₂CH═CH₂ CH═CHCONHCH(CH₃)CO₂Et 120 CH₂OCH₂CH═CH₂ CH═CHCONHCH(CH₃)CO₂H 121 CH₂CH₂CH₂CH₂OCH₃ CH═CHCONHCH(CH₃)CO₂Et 122 CH₂CH₂CH₂CH₂OCH₃ CH═CHCONHCH(CH₃)CO₂H 123 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH═CHCONHCH(CH₃)CO₂Et 124 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH═CHCONHCH(CH₃)CO₂H 125 CH₃ CH═CHCONHCH(CH₃)CO₂Et 126 CH₃ CH═CHCONHCH(CH₃)CO₂H 127 H CONHCH(CH₂C₆H₅)CO₂Et 128 H CONHCH(CH₂C₆H₅)CO₂H 129 CH₂OCH₃ CONHCH(CH₂C₆H₅)CO₂Et 130 CH₂OCH₃ CONHCH(CH₂C₆H₅)CO₂H 131 CH₂OCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂Et 132 CH₂OCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂H 133 CH₂OCH₂CH═CH₂ CONHCH(CH₂C₆H₅)CO₂Et 134 CH₂OCH₂CH═CH₂ CONHCH(CH₂C₆H₅)CO₂H 135 CH₂CH₂CH₂CH₂OCH₃ CONHCH(CH₂C₆H₅)CO₂Et 136 CH₂CH₂CH₂CH₂OCH₃ CONHCH(CH₂C₆H₅)CO₂H 137 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂Et 138 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂H 139 CH₃ CONHCH(CH₂C₆H₅)CO₂Et 140 CH₃ CONHCH(CH₂C₆H₅)CO₂H 141 CH₂NH₂ CO₂Et 142 CH₂NH₂ CO₂H 143 CH₂NH₂ CH₂CO₂Et 144 CH₂NH₂ CH₂CO₂H 145 CH₂NH₂ CH₂OCH₂CH═CHCO₂Et 146 CH₂NH₂ CH₂OCH₂CH═CHCO₂H 147 CH₂NH₂ CH₂OCH₂CO₂Et 148 CH₂NH₂ CH₂OCH₂CO₂H 149 CH₂NH₂ CH═CHCO₂Et 150 CH₂NH₂ CH═CHCO₂H 151 CH₂NH₂ C₆H₄CO₂Et 152 CH₂NH₂ C₆H₄CO₂H 153 CH₂NH₂ OCH₂PO(OEt)₂ 154 CH₂NH₂ OCH₂PO(OH)₂ 155 CH₂NH₂ CH═CHCONHCH(CH₃)CO₂Et 156 CH₂NH₂ CH═CHCONHCH(CH₃)CO₂H 157 CH₂NH₂ CH═CHCONHCH(CH₃)CO₂Et 158 CH₂NH₂ CH═CHCONHCH(CH₃)CO₂H 159 CH₂NHCH₂C₆H₅ CO₂Et 160 CH₂NHCH₂C₆H₅ CO₂H 161 CH₂NHCH₂C₆H₅ CH₂CO₂Et 162 CH₂NHCH₂C₆H₅ CH₂CO₂H 163 CH₂NHCH₂C₆H₅ CH₂OCH₂CH═CHCO₂Et 164 CH₂NHCH₂C₆H₅ CH₂OCH₂CH═CHCO₂H 165 CH₂NHCH₂C₆H₅ CH₂OCH₂CO₂Et 166 CH₂NHCH₂C₆H₅ CH₂OCH₂CO₂H 167 CH₂NHCH₂C₆H₅ CH═CHCO₂Et 168 CH₂NHCH₂C₆H₅ CH═CHCO₂H 169 CH₂NHCH₂C₆H₅ C₆H₄CO₂Et 170 CH₂NHCH₂C₆H₅ C₆H₄CO₂H 171 CH₂NHCH₂C₆H₅ OCH₂PO(OEt)₂ 172 CH₂NHCH₂C₆H₅ OCH₂PO(OH)₂ 173 CH₂NHCH₂C₆H₅ CH═CHCONH(CH₃)CO₂Et 174 CH₂NHCH₂C₆H₅ CH═CHCONH(CH₃)CO₂H 175 CH₂NHCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂Et 176 CH₂NHCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂H 177 CH₂NHCH₂CH═CH₂ CO₂Et 178 CH₂NHCH₂CH═CH₂ CO₂H 179 CH₂NHCH₂CH═CH₂ CH₂CO₂Et 180 CH₂NHCH₂CH═CH₂ CH₂CO₂H 181 CH₂NHCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂Et 182 CH₂NHCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂H 183 CH₂NHCH₂CH═CH₂ CH₂OCH₂CO₂Et 184 CH₂NHCH₂CH═CH₂ CH₂OCH₂CO₂H 185 CH₂NHCH₂CH═CH₂ CH═CHCO₂Et 186 CH₂NHCH₂CH═CH₂ CH═CHCO₂H 187 CH₂NHCH₂CH═CH₂ C₆H₄CO₂Et 188 CH₂NHCH₂CH═CH₂ C₆H₄CO₂H 189 CH₂NHCH₂CH═CH₂ OCH₂PO(OEt)₂ 190 CH₂NHCH₂CH═CH₂ OCH₂PO(OH)₂ 191 CH₂NHCH₂CH═CH₂ CH═CHCONHCH(CH₃)CO₂Et 192 CH₂NHCH₂CH═CH₂ CH═CHCONHCH(CH₃)CO₂H 193 CH₂NHCH₂CH═CH₂ CONHCH(CH₂C₆H₅)CO₂Et 194 CH₂NHCH₂CH═CH₂ CONHCH(CH₂C₆H₅)CO₂H 195 CH₂N(CH₃)₂ CO₂Et 196 CH₂N(CH₃)₂ CO₂H 197 CH₂N(CH₃)₂ CH₂CO₂Et 198 CH₂N(CH₃)₂ CH₂CO₂H 199 CH₂N(CH₃)₂ CH₂OCH₂CH═CHCO₂Et 200 CH₂N(CH₃)₂ CH₂OCH₂CH═CHCO₂H 201 CH₂N(CH₃)₂ CH₂OCH₂CO₂Et 202 CH₂N(CH₃)₂ CH₂OCH₂CO₂H 203 CH₂N(CH₃)₂ CH═CHCO₂Et 204 CH₂N(CH₃)₂ CH═CHCO₂H 205 CH₂N(CH₃)₂ C₆H₄CO₂Et 206 CH₂N(CH₃)₂ C₆H₄CO₂H 207 CH₂N(CH₃)₂ OCH₂PO(OEt)₂ 208 CH₂N(CH₃)₂ OCH₂PO(OH)₂ 209 CH₂N(CH₃)₂ CH═CHCONHCH(CH₃)CO₂Et 210 CH₂N(CH₃)₂ CH═CHCONHCH(CH₃)CO₂H 211 CH₂N(CH₃)₂ CONHCH(CH₂C₆H₅)CO₂Et 212 CH₂N(CH₃)₂ CONHCH(CH₂C₆H₅)CO₂H 213 CH₂NHCH₂CONH₂ CO₂Et 214 CH₂NHCH₂CONH₂ CO₂H 215 CH₂NHCH₂CONH₂ CH₂CO₂Et 216 CH₂NHCH₂CONH₂ CH₂CO₂H 217 CH₂NHCH₂CONH₂ CH₂OCH₂CH═CHCO₂Et 218 CH₂NHCH₂CONH₂ CH₂OCH₂CH═CHCO₂H 219 CH₂NHCH₂CONH₂ CH₂OCH₂CO₂Et 220 CH₂NHCH₂CONH₂ CH₂OCH₂CO₂H 221 CH₂NHCH₂CONH₂ CH═CHCO₂Et 222 CH₂NHCH₂CONH₂ CH═CHCO₂H 223 CH₂NHCH₂CONH₂ C₆H₄CO₂Et 224 CH₂NHCH₂CONH₂ C₆H₄CO₂H 225 CH₂NHCH₂CONH₂ OCH₂PO(OEt)₂ 226 CH₂NHCH₂CONH₂ OCH₂PO(OH)₂ 227 CH₂NHCH₂CONH₂ CH═CHCONHCH(CH₃)CO₂Et 228 CH₂NHCH₂CONH₂ CH═CHCONHCH(CH₃)CO₂H 229 CH₂NHCH₂CONH₂ CONHCH(CH₂C₆H₅)CO₂Et 230 CH₂NHCH₂CONH₂ CONHCH(CH₂C₆H₅)CO₂H

TABLE IIIb

Ex. # Q X 1 H CO₂Et 2 H CO₂H 3 CH₂OCH₃ CO₂Et 4 CH₂OCH₃ CO₂H 5 CH₂OCH₂C₆H₅ CO₂Et 6 CH₂OCH₂C₆H₅ CO₂H 7 CH₂OCH₂CH═CH₂ CO₂Et 8 CH₂OCH₂CH═CH₂ CO₂H 9 CH₂CH₂CH₂CH₂OCH₃ CO₂Et 10 CH₂CH₂CH₂CH₂OCH₃ CO₂H 11 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CO₂Et 12 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CO₂H 13 CH₃ CO₂Et 14 CH₃ CO₂H 15 H CH₂CO₂Et 16 H CH₂CO₂H 17 CH₂OCH₃ CH₂CO₂Et 18 CH₂OCH₃ CH₂CO₂H 19 CH₂OCH₂C₆H₅ CH₂CO₂Et 20 CH₂OCH₂C₆H₅ CH₂CO₂H 21 CH₂OCH₂CH═CH₂ CH₂CO₂Et 22 CH₂OCH₂CH═CH₂ CH₂CO₂H 23 CH₂CH₂CH₂CH₂OCH₃ CH₂CO₂Et 24 CH₂CH₂CH₂CH₂OCH₃ CH₂CO₂H 25 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂CO₂Et 26 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂CO₂H 27 CH₃ CH₂CO₂Et 28 CH₃ CH₂CO₂H 29 H CH₂OCH₂CH═CHCO₂Et 30 H CH₂OCH₂CH═CHCO₂H 31 CH₂OCH₃ CH₂OCH₂CH═CHCO₂Et 32 CH₂OCH₃ CH₂OCH₂CH═CHCO₂H 33 CH₂OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂Et 34 CH₂OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂H 35 CH₂OCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂Et 36 CH₂OCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂H 37 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂CH═CHCO₂Et 38 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂CH═CHCO₂H 39 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂CH═CHCO₂Et 40 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂CH═CHOC₂H 41 CH₃ CH₂OCH₂CH═CHCO₂Et 42 CH₃ CH₂OCH₂CH═CHCO₂H 43 H CH₂OCH₂CO₂Et 44 H CH₂OCH₂CO₂H 45 CH₂OCH₃ CH₂OCH₂CO₂Et 46 CH₂OCH₃ CH₂OCH₂CO₂H 47 CH₂OCH₂C₆H₅ CH₂OCH₂CO₂Et 48 CH₂OCH₂C₆H₅ CH₂OCH₂CO₂H 49 CH₂OCH₂CH═CH₂ CH₂OCH₂CO₂Et 50 CH₂OCH₂CH═CH₂ CH₂OCH₂CO₂H 51 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂CO₂Et 52 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂CO₂H 53 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂CO₂Et 54 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂CO₂H 55 CH₃ CH₂OCH₂CO₂Et 56 CH₃ CH₂OCH₂CO₂H 57 H CH₂OCH₂PO(OEt)₂ 58 H CH₂OCH₂PO(OH)₂ 59 CH₂OCH₃ CH₂OCH₂PO(OEt)₂ 60 CH₂OCH₃ CH₂OCH₂PO(OH)₂ 61 CH₂OCH₂C₆H₅ CH₂OCH₂PO(OEt)₂ 62 CH₂OCH₂C₆H₅ CH₂OCH₂PO(OH)₂ 63 CH₂OCH₂CH═CH₂ CH₂OCH₂PO(OEt)₂ 64 CH₂OCH₂CH═CH₂ CH₂OCH₂PO(OH)₂ 65 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂PO(OEt)₂ 66 CH₂CH₂CH₂CH₂OCH₃ CH₂OCH₂PO(OH)₂ 67 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂PO(OEt)₂ 68 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH₂OCH₂PO(OH)₂ 69 CH₃ CH₂OCH₂PO(OEt)₂ 70 CH₃ CH₂OCH₂PO(OH)₂ 71 H CH═CHCO₂Et 72 H CH═CHCO₂H 73 CH₂OCH₃ CH═CHCO₂Et 74 CH₂OCH₃ CH═CHCO₂H 75 CH₂OCH₂C₆H₅ CH═CHCO₂Et 76 CH₂OCH₂C₆H₅ CH═CHCO₂H 77 CH₂OCH₂CH═CH₂ CH═CHCO₂Et 78 CH₂OCH₂CH═CH₂ CH═CHCO₂H 79 CH₂CH₂CH₂CH₂OCH₃ CH═CHCO₂Et 80 CH₂CH₂CH₂CH₂OCH₃ CH═CHCO₂H 81 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH═CHCO₂Et 82 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH═CHCO₂H 83 CH₃ CH═CHCO₂Et 84 CH₃ CH═CHCO₂H 85 H C₆H₄CO₂Et 86 H C₆H₄CO₂H 87 CH₂OCH₃ C₆H₄CO₂Et 88 CH₂OCH₃ C₆H₄CO₂H 89 CH₂OCH₂C₆H₅ C₆H₄CO₂Et 90 CH₂OCH₂C₆H₅ C₆H₄CO₂H 91 CH₂OCH₂CH═CH₂ C₆H₄CO₂Et 92 CH₂OCH₂CH═CH₂ C₆H₄CO₂H 93 CH₂CH₂CH₂CH₂OCH₃ C₆H₄CO₂Et 94 CH₂CH₂CH₂CH₂OCH₃ C₆H₄CO₂H 95 CH₂CH₂CH₂CH₂OCH₂C₆H₅ C₆H₄CO₂Et 96 CH₂CH₂CH₂CH₂OCH₂C₆H₅ C₆H₄CO₂H 97 CH₃ C₆H₄CO₂Et 98 CH₃ C₆H₄CO₂H 99 H OCH₂PO(OEt)₂ 100 H OCH₂PO(OH)₂ 101 CH₂OCH₃ OCH₂PO(OEt)₂ 102 CH₂OCH₃ OCH₂PO(OH)₂ 103 CH₂OCH₂C₆H₅ OCH₂PO(OEt)₂ 104 CH₂OCH₂C₆H₅ OCH₂PO(OH)₂ 105 CH₂OCH₂CH═CH₂ OCH₂PO(OEt)₂ 106 CH₂OCH₂CH═CH₂ OCH₂PO(OH)₂ 107 CH₂CH₂CH₂CH₂OCH₃ OCH₂PO(OEt)₂ 108 CH₂CH₂CH₂CH₂OCH₃ OCH₂PO(OH)₂ 109 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂PO(OEt)₂ 110 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂PO(OH)₂ 111 CH₃ OCH₂PO(OEt)₂ 112 CH₃ OCH₂PO(OH)₂ 113 H CH═CHCONHCH(CH₃)CO₂Et 114 H CH═CHCONHCH(CH₃)CO₂H 115 CH₂OCH₃ CH═CHCONHCH(CH₃)CO₂Et 116 CH₂OCH₃ CH═CHCONHCH(CH₃)CO₂H 117 CH₂OCH₂C₆H₅ CH═CHCONHCH(CH₃)CO₂Et 118 CH₂OCH₂C₆H₅ CH═CHCONHCH(CH₃)CO₂H 119 CH₂OCH₂CH═CH₂ CH═CHCONHCH(CH₃)CO₂Et 120 CH₂OCH₂CH═CH₂ CH═CHCONHCH(CH₃)CO₂H 121 CH₂CH₂CH₂CH₂OCH₃ CH═CHCONHCH(CH₃)CO₂Et 122 CH₂CH₂CH₂CH₂OCH₃ CH═CHCONHCH(CH₃)CO₂H 123 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH═CHCONHCH(CH₃)CO₂Et 124 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CH═CHCONHCH(CH₃)CO₂H 125 CH₃ CH═CHCONHCH(CH₃)CO₂Et 126 CH₃ CH═CHCONHCH(CH₃)CO₂H 127 H CONHCH(CH₂C₆H₅)CO₂Et 128 H CONHCH(CH₂C₆H₅)CO₂H 129 CH₂OCH₃ CONHCH(CH₂C₆H₅)CO₂Et 130 CH₂OCH₃ CONHCH(CH₂C₆H₅)CO₂H 131 CH₂OCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂Et 132 CH₂OCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂H 133 CH₂OCH₂CH═CH₂ CONHCH(CH₂C₆H₅)CO₂Et 134 CH₂OCH₂CH═CH₂ CONHCH(CH₂C₆H₅)CO₂H 135 CH₂CH₂CH₂CH₂OCH₃ CONHCH(CH₂C₆H₅)CO₂Et 136 CH₂CH₂CH₂CH₂OCH₃ CONHCH(CH₂C₆H₅)CO₂H 137 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂Et 138 CH₂CH₂CH₂CH₂OCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂H 139 CH₃ CONHCH(CH₂C₆H₅)CO₂Et 140 CH₃ CONHCH(CH₂C₆H₅)CO₂H 141 CH₂NH₂ CO₂Et 142 CH₂NH₂ CO₂H 143 CH₂NH₂ CH₂CO₂Et 144 CH₂NH₂ CH₂CO₂H 145 CH₂NH₂ CH₂OCH₂CH═CHCO₂Et 146 CH₂NH₂ CH₂OCH₂CH═CHCO₂H 147 CH₂NH₂ CH₂OCH₂CO₂Et 148 CH₂NH₂ CH₂OCH₂CO₂H 149 CH₂NH₂ CH═CHCO₂Et 150 CH₂NH₂ CH═CHCO₂H 151 CH₂NH₂ C₆H₄CO₂Et 152 CH₂NH₂ C₆H₄CO₂H 153 CH₂NH₂ OCH₂PO(OEt)₂ 154 CH₂NH₂ OCH₂PO(OH)₂ 155 CH₂NH₂ CH═CHCONHCH(CH₃)CO₂Et 156 CH₂NH₂ CH═CHCONHCH(CH₃)CO₂H 157 CH₂NH₂ CH═CHCONHCH(CH₃)CO₂Et 158 CH₂NH₂ CH═CHCONHCH(CH₃)CO₂H 159 CH₂NHCH₂C₆H₅ CO₂Et 160 CH₂NHCH₂C₆H₅ CO₂H 161 CH₂NHCH₂C₆H₅ CH₂CO₂Et 162 CH₂NHCH₂C₆H₅ CH₂CO₂H 163 CH₂NHCH₂C₆H₅ CH₂OCH₂CH═CHCO₂Et 164 CH₂NHCH₂C₆H₅ CH₂OCH₂CH═CHCO₂H 165 CH₂NHCH₂C₆H₅ CH₂OCH₂CO₂Et 166 CH₂NHCH₂C₆H₅ CH₂OCH₂CO₂H 167 CH₂NHCH₂C₆H₅ CH═CHCO₂Et 168 CH₂NHCH₂C₆H₅ CH═CHCO₂H 169 CH₂NHCH₂C₆H₅ C₆H₄CO₂Et 170 CH₂NHCH₂C₆H₅ C₆H₄CO₂H 171 CH₂NHCH₂C₆H₅ OCH₂PO(OEt)₂ 172 CH₂NHCH₂C₆H₅ OCH₂PO(OH)₂ 173 CH₂NHCH₂C₆H₅ CH═CHCONH(CH₃)CO₂Et 174 CH₂NHCH₂C₆H₅ CH═CHCONH(CH₃)CO₂H 175 CH₂NHCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂Et 176 CH₂NHCH₂C₆H₅ CONHCH(CH₂C₆H₅)CO₂H 177 CH₂NHCH₂CH═CH₂ CO₂Et 178 CH₂NHCH₂CH═CH₂ CO₂H 179 CH₂NHCH₂CH═CH₂ CH₂CO₂Et 180 CH₂NHCH₂CH═CH₂ CH₂CO₂H 181 CH₂NHCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂Et 182 CH₂NHCH₂CH═CH₂ CH₂OCH₂CH═CHCO₂H 183 CH₂NHCH₂CH═CH₂ CH₂OCH₂CO₂Et 184 CH₂NHCH₂CH═CH₂ CH₂OCH₂CO₂H 185 CH₂NHCH₂CH═CH₂ CH═CHCO₂Et 186 CH₂NHCH₂CH═CH₂ CH═CHCO₂H 187 CH₂NHCH₂CH═CH₂ C₆H₄CO₂Et 188 CH₂NHCH₂CH═CH₂ C₆H₄CO₂H 189 CH₂NHCH₂CH═CH₂ OCH₂PO(OEt)₂ 190 CH₂NHCH₂CH═CH₂ OCH₂PO(OH)₂ 191 CH₂NHCH₂CH═CH₂ CH═CHCONHCH(CH₃)CO₂Et 192 CH₂NHCH₂CH═CH₂ CH═CHCONHCH(CH₃)CO₂H 193 CH₂NHCH₂CH═CH₂ CONHCH(CH₂C₆H₅)CO₂Et 194 CH₂NHCH₂CH═CH₂ CONHCH(CH₂C₆H₅)CO₂H 195 CH₂N(CH₃)₂ CO₂Et 196 CH₂N(CH₃)₂ CO₂H 197 CH₂N(CH₃)₂ CH₂CO₂Et 198 CH₂N(CH₃)₂ CH₂CO₂H 199 CH₂N(CH₃)₂ CH₂OCH₂CH═CHCO₂Et 200 CH₂N(CH₃)₂ CH₂OCH₂CH═CHCO₂H 201 CH₂N(CH₃)₂ CH₂OCH₂CO₂Et 202 CH₂N(CH₃)₂ CH₂OCH₂CO₂H 203 CH₂N(CH₃)₂ CH═CHCO₂Et 204 CH₂N(CH₃)₂ CH═CHCO₂H 205 CH₂N(CH₃)₂ C₆H₄CO₂Et 206 CH₂N(CH₃)₂ C₆H₄CO₂H 207 CH₂N(CH₃)₂ OCH₂PO(OEt)₂ 208 CH₂N(CH₃)₂ OCH₂PO(OH)₂ 209 CH₂N(CH₃)₂ CH═CHCONHCH(CH₃)CO₂Et 210 CH₂N(CH₃)₂ CH═CHCONHCH(CH₃)CO₂H 211 CH₂N(CH₃)₂ CONHCH(CH₂C₆H₅)CO₂Et 212 CH₂N(CH₃)₂ CONHCH(CH₂C₆H₅)CO₂H 213 CH₂NHCH₂CONH₂ CO₂Et 214 CH₂NHCH₂CONH₂ CO₂H 215 CH₂NHCH₂CONH₂ CH₂CO₂Et 216 CH₂NHCH₂CONH₂ CH₂CO₂H 217 CH₂NHCH₂CONH₂ CH₂OCH₂CH═CHCO₂Et 218 CH₂NHCH₂CONH₂ CH₂OCH₂CH═CHCO₂H 219 CH₂NHCH₂CONH₂ CH₂OCH₂CO₂Et 220 CH₂NHCH₂CONH₂ CH₂OCH₂CO₂H 221 CH₂NHCH₂CONH₂ CH═CHCO₂Et 222 CH₂NHCH₂CONH₂ CH═CHCO₂H 223 CH₂NHCH₂CONH₂ C₆H₄CO₂Et 224 CH₂NHCH₂CONH₂ C₆H₄CO₂H 225 CH₂NHCH₂CONH₂ OCH₂PO(OEt)₂ 226 CH₂NHCH₂CONH₂ OCH₂PO(OH)₂ 227 CH₂NHCH₂CONH₂ CH═CHCONHCH(CH₃)CO₂Et 228 CH₂NHCH₂CONH₂ CH═CHCONHCH(CH₃)CO₂H 229 CH₂NHCH₂CONH₂ CONHCH(CH₂C₆H₅)CO₂Et 230 CH₂NHCH₂CONH₂ CONHCH(CH₂C₆H₅)CO₂H

TABLE IV

Ex. # Q X R¹ 1 H OSO₂CH₃ H 2 H OSO₂CH₃ CH₃ 3 CH₂OCH₃ OSO₂CH₃ H 4 CH₂OCH₃ OSO₂CH₃ CH₃ 5 CH₂OCH₂C₆H₅ OSO₂CH₃ H 6 CH₂OCH₂C₆H₅ OSO₂CH₃ CH₃ 7 CH₂OCH₂CH═CH₂ OSO₂CH₃ H 8 CH₂OCH₂CH═CH₂ OSO₂CH₃ CH₃ 9 CH₂CH₂CH₂CH₂OCH₃ OSO₂CH₃ H 10 CH₂CH₂CH₂CH₂OCH₃ OSO₂CH₃ CH₃ 11 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OSO₂CH₃ H 12 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OSO₂CH₃ CH₃ 13 CH₃ OSO₂CH₃ H 14 CH₃ OSO₂CH₃ CH₃ 15 H NHSO₂CH₃ H 16 H NHSO₂CH₃ CH₃ 17 CH₂OCH₃ NHSO₂CH₃ H 18 CH₂OCH₃ NHSO₂CH₃ CH₃ 19 CH₂OCH₂C₆H₅ NHSO₂CH₃ H 20 CH₂OCH₂C₆H₅ NHSO₂CH₃ CH₃ 21 CH₂OCH₂CH═CH₂ NHSO₂CH₃ H 22 CH₂OCH₂CH═CH₂ NHSO₂CH₃ CH₃ 23 CH₂CH₂CH₂CH₂OCH₃ NHSO₂CH₃ H 24 CH₂CH₂CH₂CH₂OCH₃ NHSO₂CH₃ CH₃ 25 CH₂CH₂CH₂CH₂OCH₂C₆H₅ NHSO₂CH₃ H 26 CH₂CH₂CH₂CH₂OCH₂C₆H₅ NHSO₂CH₃ CH₃ 27 CH₃ NHSO₂CH₃ H 28 CH₃ NHSO₂CH₃ CH₃ 29 H OH H 30 H OH CH₃ 31 CH₂OCH₃ OH H 32 CH₂OCH₃ OH CH₃ 33 CH₂OCH₂C₆H₅ OH H 34 CH₂OCH₂C₆H₅ OH CH₃ 35 CH₂OCH₂CH═CH₂ OH H 36 CH₂OCH₂CH═CH₂ OH CH₃ 37 CH₂CH₂CH₂CH₂OCH₃ OH H 38 CH₂CH₂CH₂CH₂OCH₃ OH CH₃ 39 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OH H 40 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OH CH₃ 41 CH₃ OH H 42 CH₃ OH CH₃ 43 H NHCH₂CONH₂ H 44 H NHCH₂CONH₂ CH₃ 45 CH₂OCH₃ NHCH₂CONH₂ H 46 CH₂OCH₃ NHCH₂CONH₂ CH₃ 47 CH₂OCH₂C₆H₅ NHCH₂CONH₂ H 48 CH₂OCH₂C₆H₅ NHCH₂CONH₂ CH₃ 49 CH₂OCH₂CH═CH₂ NHCH₂CONH₂ H 50 CH₂OCH₂CH═CH₂ NHCH₂CONH₂ CH₃ 51 CH₂CH₂CH₂CH₂OCH₃ NHCH₂CONH₂ H 52 CH₂CH₂CH₂CH₂OCH₃ NHCH₂CONH₂ CH₃ 53 CH₂CH₂CH₂CH₂OCH₂C₆H₅ NHCH₂CONH₂ H 54 CH₂CH₂CH₂CH₂OCH₂C₆H₅ NHCH₂CONH₂ CH₃ 55 CH₃ NHCH₂CONH₂ H 56 CH₃ NHCH₂CONH₂ CH₃ 57 H NHCH₂CH(CO₂H)NHAc H 58 H NHCH₂CH(CO₂H)NHAc CH₃ 59 CH₂OCH₃ NHCH₂CH(CO₂H)NHAc H 60 CH₂OCH₃ NHCH₂CH(CO₂H)NHAc CH₃ 61 CH₂OCH₂C₆H₅ NHCH₂CH(CO₂H)NHAc H 62 CH₂OCH₂C₆H₅ NHCH₂CH(CO₂H)NHAc CH₃ 63 CH₂OCH₂CH═CH₂ NHCH₂CH(CO₂H)NHAc H 64 CH₂OCH₂CH═CH₂ NHCH₂CH(CO₂H)NHAc CH₃ 65 CH₂CH₂CH₂CH₂OCH₃ NHCH₂CH(CO₂H)NHAc H 66 CH₂CH₂CH₂CH₂OCH₃ NHCH₂CH(CO₂H)NHAc CH₃ 67 CH₂CH₂CH₂CH₂OCH₂C₆H₅ NHCH₂CH(CO₂H)NHAc H 68 CH₂CH₂CH₂CH₂OCH₂C₆H₅ NHCH₂CH(CO₂H)NHAc CH₃ 69 CH₃ NHCH₂CH(CO₂H)NHAc H 70 CH₃ NHCH₂CH(CO₂H)NHAc CH₃ 71 H NHCH₂CH(CO₂CH₃)NHAc H 72 H NHCH₂CH(CO₂CH₃)NHAc CH₃ 73 CH₂OCH₃ NHCH₂CH(CO₂CH₃)NHAc H 74 CH₂OCH₃ NHCH₂CH(CO₂CH₃)NHAc CH₃ 75 CH₂OCH₂C₆H₅ NHCH₂CH(CO₂CH₃)NHAc H 76 CH₂OCH₂C₆H₅ NHCH₂CH(CO₂CH₃)NHAc CH₃ 77 CH₂OCH₂CH═CH₂ NHCH₂CH(CO₂CH₃)NHAc H 78 CH₂OCH₂CH═CH₂ NHCH₂CH(CO₂CH₃)NHAc CH₃ 79 CH₂CH₂CH₂CH₂OCH₃ NHCH₂CH(CO₂CH₃)NHAc H 80 CH₂CH₂CH₂CH₂OCH₃ NHCH₂CH(CO₂CH₃)NHAc CH₃ 81 CH₂CH₂CH₂CH₂OCH₂C₆H₅ NHCH₂CH(CO₂CH₃)NHAc H 82 CH₂CH₂CH₂CH₂OCH₂C₆H₅ NHCH₂CH(CO₂CH₃)NHAc CH₃ 83 CH₃ NHCH₂CH(CO₂CH₃)NHAc H 84 CH₃ NHCH₂CH(CO₂CH₃)NHAc CH₃ 85 H SO₂NHCH₃ H 86 H SO₂NHCH₃ CH₃ 87 CH₂OCH₃ SO₂NHCH₃ H 88 CH₂OCH₃ SO₂NHCH₃ CH₃ 89 CH₂OCH₂C₆H₅ SO₂NHCH₃ H 90 CH₂OCH₂C₆H₅ SO₂NHCH₃ CH₃ 91 CH₂OCH₂CH═CH₂ SO₂NHCH₃ H 92 CH₂OCH₂CH═CH₂ SO₂NHCH₃ CH₃ 93 CH₂CH₂CH₂CH₂OCH₃ SO₂NHCH₃ H 94 CH₂CH₂CH₂CH₂OCH₃ SO₂NHCH₃ CH₃ 95 CH₂CH₂CH₂CH₂OCH₂C₆H₅ SO₂NHCH₃ H 96 CH₂CH₂CH₂CH₂OCH₂C₆H₅ SO₂NHCH₃ CH₃ 97 CH₃ SO₂NHCH₃ H 98 CH₃ SO₂NHCH₃ CH₃ 99 H OCH₂CHN⁺⁽CH₃)₃Br⁻ H 100 H OCH₂CHN⁺⁽CH₃)₃Br⁻ CH₃ 101 CH₂OCH₃ OCH₂CHN⁺⁽CH₃)₃Br⁻ H 102 CH₂OCH₃ OCH₂CHN⁺⁽CH₃)₃Br⁻ CH₃ 103 CH₂OCH₂C₆H₅ OCH₂CHN⁺⁽CH₃)₃Br⁻ H 104 CH₂OCH₂C₆H₅ OCH₂CHN⁺⁽CH₃)₃Br⁻ CH₃ 105 CH₂OCH₂CH═CH₂ OCH₂CHN⁺⁽CH₃)₃Br⁻ H 106 CH₂OCH₂CH═CH₂ OCH₂CHN⁺⁽CH₃)₃Br⁻ CH₃ 107 CH₂CH₂CH₂CH₂OCH₃ OCH₂CHN⁺⁽CH₃)₃Br⁻ H 108 CH₂CH₂CH₂CH₂OCH₃ OCH₂CHN⁺⁽CH₃)₃Br⁻ CH₃ 109 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂CHN⁻⁽CH₃)₃Br⁻ H 110 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂CHN⁺⁽CH₃)₃Br⁻ CH₃ 111 CH₃ OCH₂CHN⁺⁽CH₃)₃Br⁻ H 112 CH₃ OCH₂CHN⁺⁽CH₃)₃Br⁻ CH₃ 113 H OCH₂CHN⁺⁽CH₃)₃Cl⁻ H 114 H OCH₂CHN⁺⁽CH₃)₃Cl⁻ CH₃ 115 CH₂OCH₃ OCH₂CHN⁺⁽CH₃)₃Cl⁻ H 116 CH₂OCH₃ OCH₂CHN⁺⁽CH₃)₃Cl⁻ CH₃ 117 CH₂OCH₂C₆H₅ OCH₂CHN⁺⁽CH₃)₃Cl⁻ H 118 CH₂OCH₂C₆H₅ OCH₂CHN⁺⁽CH₃)₃Cl⁻ CH₃ 119 CH₂OCH₂CH═CH₂ OCH₂CHN⁺⁽CH₃)₃Cl⁻ H 120 CH₂OCH₂CH═CH₂ OCH₂CHN⁺⁽CH₃)₃Cl⁻ CH₃ 121 CH₂CH₂CH₂CH₂OCH₃ OCH₂CHN⁺⁽CH₃)₃Cl⁻ H 122 CH₂CH₂CH₂CH₂OCH₃ OCH₂CHN⁺⁽CH₃)₃Cl⁻ CH₃ 123 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂CHN⁺⁽CH₃)₃Cl⁻ H 124 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂CHN⁺⁽CH₃)₃Cl⁻ CH₃ 125 CH₃ OCH₂CHN⁺⁽CH₃)₃Cl⁻ H 126 CH₃ OCH₂CHN⁺⁽CH₃)₃Cl⁻ CH₃ 127 CH₂N(CH₃)₂ NHSO₂CH₃ H 128 CH₂N(CH₃)₂ NHSO₂CH₃ CH₃ 129 CH₂NHCH₂C₆H₅ NHSO₂CH₃ H 130 CH₂NHCH₂C₆H₅ NHSO₂CH₃ CH₃ 131 CH₂NHCH₂CH═CH₂ NHSO₂CH₃ H 132 CH₂NHCH₂CH═CH₂ NHSO₂CH₃ CH₃ 133 CH₂N(CH₃)₂ SO₂NHCH₃ H 134 CH₂N(CH₃)₂ SO₂NHCH₃ CH₃ 135 CH₂NHCH₂C₆H₅ SO₂NHCH₃ H 136 CH₂NHCH₂C₆H₅ SO₂NHCH₃ CH₃ 137 CH₂NHCH₂CH═CH₂ SO₂NHCH₃ H 138 CH₂NHCH₂CH═CH₂ SO₂NHCH₃ CH₃ 139 H OCH₂C₆H₄NHSO₂CH₃ H 140 H OCH₂C₆H₄NHSO₂CH₃ CH₃ 141 CH₂OCH₃ OCH₂C₆H₄NHSO₂CH₃ H 142 CH₂OCH₃ OCH₂C₆H₄NHSO₂CH₃ CH₃ 143 CH₂OCH₂C₆H₅ OCH₂C₆H₄NHSO₂CH₃ H 144 CH₂OCH₂C₆H₅ OCH₂C₆H₄NHSO₂CH₃ CH₃ 145 CH₂OCH₂CH═CH₂ OCH₂C₆H₄NHSO₂CH₃ H 146 CH₂OCH₂CH═CH₂ OCH₂C₆H₄NHSO₂CH₃ CH₃ 147 CH₂CH₂CH₂CH₂OCH₃ OCH₂C₆H₄NHSO₂CH₃ H 148 CH₂CH₂CH₂CH₂OCH₃ OCH₂C₆H₄NHSO₂CH₃ CH₃ 149 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂C₆H₄NHSO₂CH₃ H 150 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂C₆H₄NHSO₂CH₃ CH₃ 151 H OCH₂C₆H₄CONH₂ H 152 H OCH₂C₆H₄CONH₂ CH₃ 153 CH₂OCH₃ OCH₂C₆H₄CONH₂ H 154 CH₂OCH₃ OCH₂C₆H₄CONH₂ CH₃ 155 CH₂OCH₂C₆H₅ OCH₂C₆H₄CONH₂ H 156 CH₂OCH₂C₆H₅ OCH₂C₆H₄CONH₂ CH₃ 157 CH₂OCH₂CH═CH₂ OCH₂C₆H₄CONH₂ H 158 CH₂OCH₂CH═CH₂ OCH₂C₆H₄CONH₂ CH₃ 159 CH₂CH₂CH₂CH₂OCH₃ OCH₂C₆H₄CONH₂ H 160 CH₂CH₂CH₂CH₂OCH₃ OCH₂C₆H₄CONH₂ CH₃ 161 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂C₆H₄CONH₂ H 162 CH₂CH₂CH₂CH₂OCH₂C₆H₅ OCH₂C₆H₄CONH₂ CH₃

TABLE Va

Ex. # X X¹ Z Q 1 H H CH₃ H 2 H H CH₂CH═CH₂ H 3 H H CH₂C≡CH H 4 H H CH₃ CH₃ 5 H H CH₂CH═CH₂ CH₃ 6 H H CH₂C≡CH CH₃ 7 H H CH₃ CH₂OCH₃ 8 H H CH₂CH═CH₂ CH₂OCH₃ 9 H H CH₂C≡CH CH₂OCH₃ 10 H H CH₃ CH₂OCH₂C₆H₅ 11 H H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 12 H H CH₂C≡CH CH₂OCH₂C₆H₅ 13 H H CH₃ CH₂OCH₂CH═CH₂ 14 H H CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 15 H H CH₂C≡CH CH₂OCH₂CH═CH₂ 16 H OCH₃ CH₃ CH₃ 17 H OCH₃ CH₂CH═CH₂ CH₃ 18 H OCH₃ CH₂C≡CH CH₃ 19 H OCH₃ CH₃ CH₂OCH₃ 20 H OCH₃ CH₂CH═CH₂ CH₂OCH₃ 21 H OCH₃ CH₂C≡CH CH₂OCH₃ 22 H OCH₃ CH₃ CH₂OCH₂C₆H₅ 23 H OCH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 24 H OCH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 25 H OCH₃ CH₃ CH₂OCH₂CH═CH₂ 26 H OCH₃ CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 27 H OCH₃ CH₂C≡CH CH₂OCH₂CH═CH₂ 28 H OCH₂C₆H₅ CH₃ H 29 H OCH₂C₆H₅ CH₂CH═CH₂ H 30 H OCH₂C₆H₅ CH₂C≡CH H 31 H OCH₂C₆H₅ CH₃ CH₂OCH₃ 32 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₃ 33 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₃ 34 H OCH₂C₆H₅ CH₃ CH₂OCH₂C₆H₅ 35 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 36 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₂C₆H₅ 37 H OCH₂C₆H₅ CH₃ CH₂OCH₂CH═CH₂ 38 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 39 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₂CH═CH₂ 40 NO₂ H CH₃ H 41 NO₂ H CH₂CH═CH₂ H 42 NO₂ H CH₂C≡CH H 43 NO₂ H CH₃ CH₃ 44 NO₂ H CH₂CH═CH₂ CH₃ 45 NO₂ H CH₂C≡CH CH₃ 46 NO₂ H CH₃ CH₂OCH₃ 47 NO₂ H CH₂CH═CH₂ CH₂OCH₃ 48 NO₂ H CH₂C≡CH CH₂OCH₃ 49 NO₂ H CH₃ CH₂OCH₂C₆H₅ 50 NO₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 51 NO₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 52 H CH₃ CH₃ H 53 H CH₃ CH₂CH═CH₂ H 54 H CH₃ CH₂C≡CH H 55 H CH₃ CH₃ CH₃ 56 H CH₃ CH₂CH═CH₂ CH₃ 57 H CH₃ CH₂C≡CH CH₃ 58 H CH₃ CH₃ CH₂OCH₃ 59 H CH₃ CH₂CH═CH₂ CH₂OCH₃ 60 H CH₃ CH₂C≡CH CH₂OCH₃ 61 H CH₃ CH₃ CH₂OCH₂C₆H₅ 62 H CH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 63 H CH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 64 H NHSO₂CH₃ CH₃ H 65 H NHSO₂CH₃ CH₂CH═CH₂ H 66 H NHSO₂CH₃ CH₂C≡CH H 67 H NHSO₂CH₃ CH₃ CH₃ 68 H NHSO₂CH₃ CH₂CH═CH₂ CH₃ 69 H NHSO₂CH₃ CH₂C≡CH CH₃ 70 H NHSO₂CH₃ CH₃ CH₂OCH₃ 71 H NHSO₂CH₃ CH₂CH═CH₂ CH₂OCH₃ 72 H NHSO₂CH₃ CH₂C≡CH CH₂OCH₃ 73 H NHSO₂CH₃ CH₃ CH₂OCH₂C₆H₅ 74 H NHSO₂CH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 75 H NHSO₂CH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 76 Cl H CH₃ H 77 Cl H CH₂CH═CH₂ H 78 Cl H CH₂C≡CH H 79 Cl H CH₃ CH₃ 80 Cl H CH₂CH═CH₂ CH₃ 81 Cl H CH₂C≡CH CH₃ 82 NO₂ H CH₃ H 83 NO₂ H CH₂CH═CH₂ H 84 NO₂ H CH₂C≡CH H 85 NO₂ H CH₃ CH₃ 86 NO₂ H CH₂CH═CH₂ CH₃ 87 NO₂ H CH₂C≡CH CH₃ 88 NO₂ H CH₃ CH₂OCH₃ 89 NO₂ H CH₂CH═CH₂ CH₂OCH₃ 90 NO₂ H CH₂C≡CH CH₂OCH₃ 91 NO₂ H CH₃ CH₂OCH₂C₆H₅ 92 NO₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 93 NO₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 94 NH₂ H CH₃ H 95 NH₂ H CH₂CH═CH₂ H 96 NH₂ H CH₂C≡CH H 97 NH₂ H CH₃ CH₃ 98 NH₂ H CH₂CH═CH₂ CH₃ 99 NH₂ H CH₂C≡CH CH₃ 100 NH₂ H CH₃ CH₂OCH₃ 101 NH₂ H CH₂CH═CH₂ CH₂OCH₃ 102 NH₂ H CH₂C≡CH CH₂OCH₃ 103 NH₂ H CH₃ CH₂OCH₂C₆H₅ 104 NH₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 105 NH₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 106 NHSO₂CH₃ H CH₃ H 107 NHSO₂CH₃ H CH₂CH═CH₂ H 108 NHSO₂CH₃ H CH₂C≡CH H 109 NHSO₂CH₃ H CH₃ CH₃ 110 NHSO₂CH₃ H CH₂CH═CH₂ CH₃ 111 NHSO₂CH₃ H CH₂C≡CH CH₃ 112 NHSO₂CH₃ H CH₃ CH₂OCH₃ 113 NHSO₂CH₃ H CH₂CH═CH₂ CH₂OCH₃ 114 NHSO₂CH₃ H CH₂C≡CH CH₂OCH₃ 115 NHSO₂CH₃ H CH₃ CH₂OCH₂C₆H₅ 116 NHSO₂CH₃ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 117 NHSO₂CH₃ H CH₂C≡CH CH₂OCH₂C₆H₅ 118 OCH₂C₆H₅ H CH₃ H 119 OCH₂C₆H₅ H CH₂CH═CH₂ H 120 OCH₂C₆H₅ H CH₂C≡CH H 121 OCH₂C₆H₅ H CH₃ CH₃ 122 OCH₂C₆H₅ H CH₂CH═CH₂ CH₃ 123 OCH₂C₆H₅ H CH₂C≡CH CH₃ 124 OCH₂C₆H₅ H CH₃ CH₂OCH₃ 125 OCH₂C₆H₅ H CH₂CH═CH₂ CH₂OCH₃ 126 OCH₂C₆H₅ H CH₂C≡CH CH₂OCH₃ 127 OCH₂C₆H₅ H CH₃ CH₂OCH₂C₆H₅ 128 OCH₂C₆H₅ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 129 OCH₂C₆H₅ H CH₂C≡CH CH₂OCH₂C₆H₅

TABLE Vb

Ex. # X X¹ Z Q 1 H H CH₃ H 2 H H CH₂CH═CH₂ H 3 H H CH₂C≡CH H 4 H H CH₃ CH₃ 5 H H CH₂CH═CH₂ CH₃ 6 H H CH₂C≡CH CH₃ 7 H H CH₃ CH₂OCH₃ 8 H H CH₂CH═CH₂ CH₂OCH₃ 9 H H CH₂C≡CH CH₂OCH₃ 10 H H CH₃ CH₂OCH₂C₆H₅ 11 H H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 12 H H CH₂C≡CH CH₂OCH₂C₆H₅ 13 H H CH₃ CH₂OCH₂CH═CH₂ 14 H H CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 15 H H CH₂C≡CH CH₂OCH₂CH═CH₂ 16 H OCH₃ CH₃ CH₃ 17 H OCH₃ CH₂CH═CH₂ CH₃ 18 H OCH₃ CH₂C≡CH CH₃ 19 H OCH₃ CH₃ CH₂OCH₃ 20 H OCH₃ CH₂CH═CH₂ CH₂OCH₃ 21 H OCH₃ CH₂C≡CH CH₂OCH₃ 22 H OCH₃ CH₃ CH₂OCH₂C₆H₅ 23 H OCH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 24 H OCH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 25 H OCH₃ CH₃ CH₂OCH₂CH═CH₂ 26 H OCH₃ CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 27 H OCH₃ CH₂C≡CH CH₂OCH₂CH═CH₂ 28 H OCH₂C₆H₅ CH₃ H 29 H OCH₂C₆H₅ CH₂CH═CH₂ H 30 H OCH₂C₆H₅ CH₂C≡CH H 31 H OCH₂C₆H₅ CH₃ CH₂OCH₃ 32 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₃ 33 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₃ 34 H OCH₂C₆H₅ CH₃ CH₂OCH₂C₆H₅ 35 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 36 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₂C₆H₅ 37 H OCH₂C₆H₅ CH₃ CH₂OCH₂CH═CH₂ 38 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 39 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₂CH═CH₂ 40 NO₂ H CH₃ H 41 NO₂ H CH₂CH═CH₂ H 42 NO₂ H CH₂C≡CH H 43 NO₂ H CH₃ CH₃ 44 NO₂ H CH₂CH═CH₂ CH₃ 45 NO₂ H CH₂C≡CH CH₃ 46 NO₂ H CH₃ CH₂OCH₃ 47 NO₂ H CH₂CH═CH₂ CH₂OCH₃ 48 NO₂ H CH₂C≡CH CH₂OCH₃ 49 NO₂ H CH₃ CH₂OCH₂C₆H₅ 50 NO₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 51 NO₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 52 H CH₃ CH₃ H 53 H CH₃ CH₂CH═CH₂ H 54 H CH₃ CH₂C≡CH H 55 H CH₃ CH₃ CH₃ 56 H CH₃ CH₂CH═CH₂ CH₃ 57 H CH₃ CH₂C≡CH CH₃ 58 H CH₃ CH₃ CH₂OCH₃ 59 H CH₃ CH₂CH═CH₂ CH₂OCH₃ 60 H CH₃ CH₂C≡CH CH₂OCH₃ 61 H CH₃ CH₃ CH₂OCH₂C₆H₅ 62 H CH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 63 H CH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 64 H NHSO₂CH₃ CH₃ H 65 H NHSO₂CH₃ CH₂CH═CH₂ H 66 H NHSO₂CH₃ CH₂C≡CH H 67 H NHSO₂CH₃ CH₃ CH₃ 68 H NHSO₂CH₃ CH₂CH═CH₂ CH₃ 69 H NHSO₂CH₃ CH₂C≡CH CH₃ 70 H NHSO₂CH₃ CH₃ CH₂OCH₃ 71 H NHSO₂CH₃ CH₂CH═CH₂ CH₂OCH₃ 72 H NHSO₂CH₃ CH₂C≡CH CH₂OCH₃ 73 H NHSO₂CH₃ CH₃ CH₂OCH₂C₆H₅ 74 H NHSO₂CH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 75 H NHSO₂CH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 76 Cl H CH₃ H 77 Cl H CH₂CH═CH₂ H 78 Cl H CH₂C≡CH H 79 Cl H CH₃ CH₃ 80 Cl H CH₂CH═CH₂ CH₃ 81 Cl H CH₂C≡CH CH₃ 82 NO₂ H CH₃ H 83 NO₂ H CH₂CH═CH₂ H 84 NO₂ H CH₂C≡CH H 85 NO₂ H CH₃ CH₃ 86 NO₂ H CH₂CH═CH₂ CH₃ 87 NO₂ H CH₂C≡CH CH₃ 88 NO₂ H CH₃ CH₂OCH₃ 89 NO₂ H CH₂CH═CH₂ CH₂OCH₃ 90 NO₂ H CH₂C≡CH CH₂OCH₃ 91 NO₂ H CH₃ CH₂OCH₂C₆H₅ 92 NO₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 93 NO₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 94 NH₂ H CH₃ H 95 NH₂ H CH₂CH═CH₂ H 96 NH₂ H CH₂C≡CH H 97 NH₂ H CH₃ CH₃ 98 NH₂ H CH₂CH═CH₂ CH₃ 99 NH₂ H CH₂C≡CH CH₃ 100 NH₂ H CH₃ CH₂OCH₃ 101 NH₂ H CH₂CH═CH₂ CH₂OCH₃ 102 NH₂ H CH₂C≡CH CH₂OCH₃ 103 NH₂ H CH₃ CH₂OCH₂C₆H₅ 104 NH₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 105 NH₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 106 NHSO₂CH₃ H CH₃ H 107 NHSO₂CH₃ H CH₂CH═CH₂ H 108 NHSO₂CH₃ H CH₂C≡CH H 109 NHSO₂CH₃ H CH₃ CH₃ 110 NHSO₂CH₃ H CH₂CH═CH₂ CH₃ 111 NHSO₂CH₃ H CH₂C≡CH CH₃ 112 NHSO₂CH₃ H CH₃ CH₂OCH₃ 113 NHSO₂CH₃ H CH₂CH═CH₂ CH₂OCH₃ 114 NHSO₂CH₃ H CH₂C≡CH CH₂OCH₃ 115 NHSO₂CH₃ H CH₃ CH₂OCH₂C₆H₅ 116 NHSO₂CH₃ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 117 NHSO₂CH₃ H CH₂C≡CH CH₂OCH₂C₆H₅ 118 OCH₂C₆H₅ H CH₃ H 119 OCH₂C₆H₅ H CH₂CH═CH₂ H 120 OCH₂C₆H₅ H CH₂C≡CH H 121 OCH₂C₆H₅ H CH₃ CH₃ 122 OCH₂C₆H₅ H CH₂CH═CH₂ CH₃ 123 OCH₂C₆H₅ H CH₂C≡CH CH₃ 124 OCH₂C₆H₅ H CH₃ CH₂OCH₃ 125 OCH₂C₆H₅ H CH₂CH═CH₂ CH₂OCH₃ 126 OCH₂C₆H₅ H CH₂C≡CH CH₂OCH₃ 127 OCH₂C₆H₅ H CH₃ CH₂OCH₂C₆H₅ 128 OCH₂C₆H₅ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 129 OCH₂C₆H₅ H CH₂C≡CH CH₂OCH₂C₆H₅

TABLE Vc

Ex. # X X¹ Z Q 1 H H CH₃ H 2 H H CH₂CH═CH₂ H 3 H H CH₂C≡CH H 4 H H CH₃ CH₃ 5 H H CH₂CH═CH₂ CH₃ 6 H H CH₂C≡CH CH₃ 7 H H CH₃ CH₂OCH₃ 8 H H CH₂CH═CH₂ CH₂OCH₃ 9 H H CH₂C≡CH CH₂OCH₃ 10 H H CH₃ CH₂OCH₂C₆H₅ 11 H H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 12 H H CH₂C≡CH CH₂OCH₂C₆H₅ 13 H H CH₃ CH₂OCH₂CH═CH₂ 14 H H CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 15 H H CH₂C≡CH CH₂OCH₂CH═CH₂ 16 H OCH₃ CH₃ CH₃ 17 H OCH₃ CH₂CH═CH₂ CH₃ 18 H OCH₃ CH₂C≡CH CH₃ 19 H OCH₃ CH₃ CH₂OCH₃ 20 H OCH₃ CH₂CH═CH₂ CH₂OCH₃ 21 H OCH₃ CH₂C≡CH CH₂OCH₃ 22 H OCH₃ CH₃ CH₂OCH₂C₆H₅ 23 H OCH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 24 H OCH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 25 H OCH₃ CH₃ CH₂OCH₂CH═CH₂ 26 H OCH₃ CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 27 H OCH₃ CH₂C≡CH CH₂OCH₂CH═CH₂ 28 H OCH₂C₆H₅ CH₃ H 29 H OCH₂C₆H₅ CH₂CH═CH₂ H 30 H OCH₂C₆H₅ CH₂C≡CH H 31 H OCH₂C₆H₅ CH₃ CH₂OCH₃ 32 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₃ 33 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₃ 34 H OCH₂C₆H₅ CH₃ CH₂OCH₂C₆H₅ 35 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 36 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₂C₆H₅ 37 H OCH₂C₆H₅ CH₃ CH₂OCH₂CH═CH₂ 38 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 39 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₂CH═CH₂ 40 NO₂ H CH₃ H 41 NO₂ H CH₂CH═CH₂ H 42 NO₂ H CH₂C≡CH H 43 NO₂ H CH₃ CH₃ 44 NO₂ H CH₂CH═CH₂ CH₃ 45 NO₂ H CH₂C≡CH CH₃ 46 NO₂ H CH₃ CH₂OCH₃ 47 NO₂ H CH₂CH═CH₂ CH₂OCH₃ 48 NO₂ H CH₂C≡CH CH₂OCH₃ 49 NO₂ H CH₃ CH₂OCH₂C₆H₅ 50 NO₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 51 NO₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 52 H CH₃ CH₃ H 53 H CH₃ CH₂CH═CH₂ H 54 H CH₃ CH₂C≡CH H 55 H CH₃ CH₃ CH₃ 56 H CH₃ CH₂CH═CH₂ CH₃ 57 H CH₃ CH₂C≡CH CH₃ 58 H CH₃ CH₃ CH₂OCH₃ 59 H CH₃ CH₂CH═CH₂ CH₂OCH₃ 60 H CH₃ CH₂C≡CH CH₂OCH₃ 61 H CH₃ CH₃ CH₂OCH₂C₆H₅ 62 H CH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 63 H CH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 64 H NHSO₂CH₃ CH₃ H 65 H NHSO₂CH₃ CH₂CH═CH₂ H 66 H NHSO₂CH₃ CH₂C≡CH H 67 H NHSO₂CH₃ CH₃ CH₃ 68 H NHSO₂CH₃ CH₂CH═CH₂ CH₃ 69 H NHSO₂CH₃ CH₂C≡CH CH₃ 70 H NHSO₂CH₃ CH₃ CH₂OCH₃ 71 H NHSO₂CH₃ CH₂CH═CH₂ CH₂OCH₃ 72 H NHSO₂CH₃ CH₂C≡CH CH₂OCH₃ 73 H NHSO₂CH₃ CH₃ CH₂OCH₂C₆H₅ 74 H NHSO₂CH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 75 H NHSO₂CH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 76 Cl H CH₃ H 77 Cl H CH₂CH═CH₂ H 78 Cl H CH₂C≡CH H 79 Cl H CH₃ CH₃ 80 Cl H CH₂CH═CH₂ CH₃ 81 Cl H CH₂C≡CH CH₃ 82 NO₂ H CH₃ H 83 NO₂ H CH₂CH═CH₂ H 84 NO₂ H CH₂C≡CH H 85 NO₂ H CH₃ CH₃ 86 NO₂ H CH₂CH═CH₂ CH₃ 87 NO₂ H CH₂C≡CH CH₃ 88 NO₂ H CH₃ CH₂OCH₃ 89 NO₂ H CH₂CH═CH₂ CH₂OCH₃ 90 NO₂ H CH₂C≡CH CH₂OCH₃ 91 NO₂ H CH₃ CH₂OCH₂C₆H₅ 92 NO₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 93 NO₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 94 NH₂ H CH₃ H 95 NH₂ H CH₂CH═CH₂ H 96 NH₂ H CH₂C≡CH H 97 NH₂ H CH₃ CH₃ 98 NH₂ H CH₂CH═CH₂ CH₃ 99 NH₂ H CH₂C≡CH CH₃ 100 NH₂ H CH₃ CH₂OCH₃ 101 NH₂ H CH₂CH═CH₂ CH₂OCH₃ 102 NH₂ H CH₂C≡CH CH₂OCH₃ 103 NH₂ H CH₃ CH₂OCH₂C₆H₅ 104 NH₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 105 NH₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 106 NHSO₂CH₃ H CH₃ H 107 NHSO₂CH₃ H CH₂CH═CH₂ H 108 NHSO₂CH₃ H CH₂C≡CH H 109 NHSO₂CH₃ H CH₃ CH₃ 110 NHSO₂CH₃ H CH₂CH═CH₂ CH₃ 111 NHSO₂CH₃ H CH₂C≡CH CH₃ 112 NHSO₂CH₃ H CH₃ CH₂OCH₃ 113 NHSO₂CH₃ H CH₂CH═CH₂ CH₂OCH₃ 114 NHSO₂CH₃ H CH₂C≡CH CH₂OCH₃ 115 NHSO₂CH₃ H CH₃ CH₂OCH₂C₆H₅ 116 NHSO₂CH₃ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 117 NHSO₂CH₃ H CH₂C≡CH CH₂OCH₂C₆H₅ 118 OCH₂C₆H₅ H CH₃ H 119 OCH₂C₆H₅ H CH₂CH═CH₂ H 120 OCH₂C₆H₅ H CH₂C≡CH H 121 OCH₂C₆H₅ H CH₃ CH₃ 122 OCH₂C₆H₅ H CH₂CH═CH₂ CH₃ 123 OCH₂C₆H₅ H CH₂C≡CH CH₃ 124 OCH₂C₆H₅ H CH₃ CH₂OCH₃ 125 OCH₂C₆H₅ H CH₂CH═CH₂ CH₂OCH₃ 126 OCH₂C₆H₅ H CH₂C≡CH CH₂OCH₃ 127 OCH₂C₆H₅ H CH₃ CH₂OCH₂C₆H₅ 128 OCH₂C₆H₅ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 129 OCH₂C₆H₅ H CH₂C≡CH CH₂OCH₂C₆H₅

TABLE Vd

Ex. # X X¹ Z Q 1 H H CH₃ H 2 H H CH₂CH═CH₂ H 3 H H CH₂C≡CH H 4 H H CH₃ CH₃ 5 H H CH₂CH═CH₂ CH₃ 6 H H CH₂C≡CH CH₃ 7 H H CH₃ CH₂OCH₃ 8 H H CH₂CH═CH₂ CH₂OCH₃ 9 H H CH₂C≡CH CH₂OCH₃ 10 H H CH₃ CH₂OCH₂C₆H₅ 11 H H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 12 H H CH₂C≡CH CH₂OCH₂C₆H₅ 13 H H CH₃ CH₂OCH₂CH═CH₂ 14 H H CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 15 H H CH₂C≡CH CH₂OCH₂CH═CH₂ 16 H OCH₃ CH₃ CH₃ 17 H OCH₃ CH₂CH═CH₂ CH₃ 18 H OCH₃ CH₂C≡CH CH₃ 19 H OCH₃ CH₃ CH₂OCH₃ 20 H OCH₃ CH₂CH═CH₂ CH₂OCH₃ 21 H OCH₃ CH₂C≡CH CH₂OCH₃ 22 H OCH₃ CH₃ CH₂OCH₂C₆H₅ 23 H OCH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 24 H OCH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 25 H OCH₃ CH₃ CH₂OCH₂CH═CH₂ 26 H OCH₃ CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 27 H OCH₃ CH₂C≡CH CH₂OCH₂CH═CH₂ 28 H OCH₂C₆H₅ CH₃ H 29 H OCH₂C₆H₅ CH₂CH═CH₂ H 30 H OCH₂C₆H₅ CH₂C≡CH H 31 H OCH₂C₆H₅ CH₃ CH₂OCH₃ 32 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₃ 33 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₃ 34 H OCH₂C₆H₅ CH₃ CH₂OCH₂C₆H₅ 35 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 36 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₂C₆H₅ 37 H OCH₂C₆H₅ CH₃ CH₂OCH₂CH═CH₂ 38 H OCH₂C₆H₅ CH₂CH═CH₂ CH₂OCH₂CH═CH₂ 39 H OCH₂C₆H₅ CH₂C≡CH CH₂OCH₂CH═CH₂ 40 NO₂ H CH₃ H 41 NO₂ H CH₂CH═CH₂ H 42 NO₂ H CH₂C≡CH H 43 NO₂ H CH₃ CH₃ 44 NO₂ H CH₂CH═CH₂ CH₃ 45 NO₂ H CH₂C≡CH CH₃ 46 NO₂ H CH₃ CH₂OCH₃ 47 NO₂ H CH₂CH═CH₂ CH₂OCH₃ 48 NO₂ H CH₂C≡CH CH₂OCH₃ 49 NO₂ H CH₃ CH₂OCH₂C₆H₅ 50 NO₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 51 NO₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 52 H CH₃ CH₃ H 53 H CH₃ CH₂CH═CH₂ H 54 H CH₃ CH₂C≡CH H 55 H CH₃ CH₃ CH₃ 56 H CH₃ CH₂CH═CH₂ CH₃ 57 H CH₃ CH₂C≡CH CH₃ 58 H CH₃ CH₃ CH₂OCH₃ 59 H CH₃ CH₂CH═CH₂ CH₂OCH₃ 60 H CH₃ CH₂C≡CH CH₂OCH₃ 61 H CH₃ CH₃ CH₂OCH₂C₆H₅ 62 H CH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 63 H CH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 64 H NHSO₂CH₃ CH₃ H 65 H NHSO₂CH₃ CH₂CH═CH₂ H 66 H NHSO₂CH₃ CH₂C≡CH H 67 H NHSO₂CH₃ CH₃ CH₃ 68 H NHSO₂CH₃ CH₂CH═CH₂ CH₃ 69 H NHSO₂CH₃ CH₂C≡CH CH₃ 70 H NHSO₂CH₃ CH₃ CH₂OCH₃ 71 H NHSO₂CH₃ CH₂CH═CH₂ CH₂OCH₃ 72 H NHSO₂CH₃ CH₂C≡CH CH₂OCH₃ 73 H NHSO₂CH₃ CH₃ CH₂OCH₂C₆H₅ 74 H NHSO₂CH₃ CH₂CH═CH₂ CH₂OCH₂C₆H₅ 75 H NHSO₂CH₃ CH₂C≡CH CH₂OCH₂C₆H₅ 76 Cl H CH₃ H 77 Cl H CH₂CH═CH₂ H 78 Cl H CH₂C≡CH H 79 Cl H CH₃ CH₃ 80 Cl H CH₂CH═CH₂ CH₃ 81 Cl H CH₂C≡CH CH₃ 82 NO₂ H CH₃ H 83 NO₂ H CH₂CH═CH₂ H 84 NO₂ H CH₂C≡CH H 85 NO₂ H CH₃ CH₃ 86 NO₂ H CH₂CH═CH₂ CH₃ 87 NO₂ H CH₂C≡CH CH₃ 88 NO₂ H CH₃ CH₂OCH₃ 89 NO₂ H CH₂CH═CH₂ CH₂OCH₃ 90 NO₂ H CH₂C≡CH CH₂OCH₃ 91 NO₂ H CH₃ CH₂OCH₂C₆H₅ 92 NO₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 93 NO₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 94 NH₂ H CH₃ H 95 NH₂ H CH₂CH═CH₂ H 96 NH₂ H CH₂C≡CH H 97 NH₂ H CH₃ CH₃ 98 NH₂ H CH₂CH═CH₂ CH₃ 99 NH₂ H CH₂C≡CH CH₃ 100 NH₂ H CH₃ CH₂OCH₃ 101 NH₂ H CH₂CH═CH₂ CH₂OCH₃ 102 NH₂ H CH₂C≡CH CH₂OCH₃ 103 NH₂ H CH₃ CH₂OCH₂C₆H₅ 104 NH₂ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 105 NH₂ H CH₂C≡CH CH₂OCH₂C₆H₅ 106 NHSO₂CH₃ H CH₃ H 107 NHSO₂CH₃ H CH₂CH═CH₂ H 108 NHSO₂CH₃ H CH₂C≡CH H 109 NHSO₂CH₃ H CH₃ CH₃ 110 NHSO₂CH₃ H CH₂CH═CH₂ CH₃ 111 NHSO₂CH₃ H CH₂C≡CH CH₃ 112 NHSO₂CH₃ H CH₃ CH₂OCH₃ 113 NHSO₂CH₃ H CH₂CH═CH₂ CH₂OCH₃ 114 NHSO₂CH₃ H CH₂C≡CH CH₂OCH₃ 115 NHSO₂CH₃ H CH₃ CH₂OCH₂C₆H₅ 116 NHSO₂CH₃ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 117 NHSO₂CH₃ H CH₂C≡CH CH₂OCH₂C₆H₅ 118 OCH₂C₆H₅ H CH₃ H 119 OCH₂C₆H₅ H CH₂CH═CH₂ H 120 OCH₂C₆H₅ H CH₂C≡CH H 121 OCH₂C₆H₅ H CH₃ CH₃ 122 OCH₂C₆H₅ H CH₂CH═CH₂ CH₃ 123 OCH₂C₆H₅ H CH₂C≡CH CH₃ 124 OCH₂C₆H₅ H CH₃ CH₂OCH₃ 125 OCH₂C₆H₅ H CH₂CH═CH₂ CH₂OCH₃ 126 OCH₂C₆H₅ H CH₂C≡CH CH₂OCH₃ 127 OCH₂C₆H₅ H CH₃ CH₂OCH₂C₆H₅ 128 OCH₂C₆H₅ H CH₂CH═CH₂ CH₂OCH₂C₆H₅ 129 OCH₂C₆H₅ H CH₂C≡CH CH₂OCH₂C₆H₅

TABLE VI

Ex. # X X¹ Q R¹ 1 H H H H 2 H H CH₃ H 3 H H CH₂OCH₃ H 4 H H CH₂OCH₂C₆H₅ H 5 H H CH₂OCH₂CH═CH₂ H 6 H OCH₃ CH₃ H 7 H OCH₃ CH₂OCH₃ H 8 H OCH₃ CH₂OCH₂C₆H₅ H 9 H OCH₃ CH₂OCH₂CH═CH₂ H 10 H OCH₂C₆H₅ H H 11 H OCH₂C₆H₅ CH₂OCH₃ H 12 H OCH₂C₆H₅ CH₂OCH₂C₆H₅ H 13 H OCH₂C₆H₅ CH₂OCH₂CH═CH₂ H 14 NO₂ H H H 15 NO₂ H CH₃ H 16 NO₂ H CH₂OCH₃ H 17 NO₂ H CH₂OCH₂C₆H₅ H 18 H CH₃ H H 19 H CH₃ CH₃ H 20 H CH₃ CH₂OCH₃ H 21 H CH₃ CH₂OCH₂C₆H₅ H 22 H NHSO₂CH₃ H H 23 H NHSO₂CH₃ CH₃ H 24 H NHSO₂CH₃ CH₂OCH₃ H 25 H NHSO₂CH₃ CH₂OCH₂C₆H₅ H 26 Cl H H H 27 Cl H CH₃ H 28 NO₂ H H H 29 NO₂ H CH₃ H 30 NO₂ H CH₂OCH₃ H 31 NO₂ H CH₂OCH₂C₆H₅ H 32 NH₂ H H H 33 NH₂ H CH₃ H 34 NH₂ H CH₂OCH₃ H 35 NH₂ H CH₂OCH₂C₆H₅ H 36 NHSO₂CH₃ H H H 37 NHSO₂CH₃ H CH₃ H 38 NHSO₂CH₃ H CH₂OCH₃ H 39 NHSO₂CH₃ H CH₂OCH₂C₆H₅ H 40 OCH₂C₆H₅ H H H 41 OCH₂C₆H₅ H CH₃ H 42 OCH₂C₆H₅ H CH₂OCH₃ H 43 OCH₂C₆H₅ H CH₂OCH₂C₆H₅ H 44 H H H CH₃ 45 H H CH₃ CH₃ 46 H H CH₂OCH₃ CH₃ 47 H H CH₂OCH₂C₆H₅ CH₃ 48 H H CH₂OCH₂CH═CH₂ CH₃ 49 H OCH₃ CH₃ CH₃ 50 H OCH₃ CH₂OCH₃ CH₃ 51 H OCH₃ CH₂OCH₂C₆H₅ CH₃ 52 H OCH₃ CH₂OCH₂CH═CH₂ CH₃ 53 H OCH₂C₆H₅ H CH₃ 54 H OCH₂C₆H₅ CH₂OCH₃ CH₃ 55 H OCH₂C₆H₅ CH₂OCH₂C₆H₅ CH₃ 56 H OCH₂C₆H₅ CH₂OCH₂CH═CH₂ CH₃ 57 NO₂ H H CH₃ 58 NO₂ H CH₃ CH₃ 59 NO₂ H CH₂OCH₃ CH₃ 60 NO₂ H CH₂OCH₂C₆H₅ CH₃ 61 H CH₃ H CH₃ 62 H CH₃ CH₃ CH₃ 63 H CH₃ CH₂OCH₃ CH₃ 64 H CH₃ CH₂OCH₂C₆H₅ CH₃ 65 H NHSO₂CH₃ H CH₃ 66 H NHSO₂CH₃ CH₃ CH₃ 67 H NHSO₂CH₃ CH₂OCH₃ CH₃ 68 H NHSO₂CH₃ CH₂OCH₂C₆H₅ CH₃ 69 Cl H H CH₃ 70 Cl H CH₃ CH₃ 71 NO₂ H H CH₃ 72 NO₂ H CH₃ CH₃ 73 NO₂ H CH₂OCH₃ CH₃ 74 NO₂ H CH₂OCH₂C₆H₅ CH₃ 75 NH₂ H H CH₃ 76 NH₂ H CH₃ CH₃ 77 NH₂ H CH₂OCH₃ CH₃ 78 NH₂ H CH₂OCH₂C₆H₅ CH₃ 79 NHSO₂CH₃ H H CH₃ 80 NHSO₂CH₃ H CH₃ CH₃ 81 NHSO₂CH₃ H CH₂OCH₃ CH₃ 82 NHSO₂CH₃ H CH₂OCH₂C₆H₅ CH₃ 83 OCH₂C₆H₅ H H CH₃ 84 OCH₂C₆H₅ H CH₃ CH₃ 85 OCH₂C₆H₅ H CH₂OCH₃ CH₃ 86 OCH₂C₆H₅ H CH₂OCH₂C₆H₅ CH₃

Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

What is claimed is:
 1. A compound of formula I or II or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein: A, A¹, A², A³, and A⁴ are independently selected from CH and CX; R, at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R¹, at each occurrence, is independently selected from (CH₂)_(m)CO₂R, C₂₋₆ alkenyl-CO₂R, (CH₂)₂CHMCONRCH₂CO₂R, CH₂CHMCONRCH₂CO₂R, CH₂CH(NHAc)CO₂R, CH₂CH(NHR)CO₂R, (CH₂)_(n)PO(OR)₂, (CH₂)₂CONRCH(OR)CO₂R, (CH₂)₂CONRC(R)₂CH₂SO₂OR, (CH₂)_(n)SO₂OR, and (CH₂)_(n)-tetrazole; R², at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; X, at each occurrence, is independently selected from H, O(CH₂CH₂O)_(q)R⁴, CONRCH(L)CO₂R, CH═CHCO₂R, OCH₂CH═CHCO₂R, CH═CHCONRCH(L)CO₂R, C₆H₄CO₂R, C₆H₄CON(R)₂, C₆H₄CONRCH(L)CO₂R, O(CH₂)_(n)CO₂R, NR(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)CON(R)₂, CH₂OCH₂CH═CHCO₂R, CH₂OCH₂CO₂R, CH₂OCH₂PO(OR)₂, O—C₂₋₆ alkenyl-CO₂R, NR—C₃₋₆ alkenyl-CO₂R, N(R)₂, NRSO₂R^(a), SO₂NRCH₃, OCH₂CHMCONRCH₂CO₂R, NRCH₂CHMCONRCH₂CO₂R, NRCH₂CH(NHAc)CO₂R, O(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, NR(CH₂)_(n)SO₂OR, OCH₂(CH₂)_(n)N⁺(CH₃)₃V⁻, CH₂N⁺(CH₃)₃V⁻, O(CH₂)_(n)-aryl, NR(CH₂)_(n)-aryl, O(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and NR(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, (CH₂)_(r)CO₂R, (CH₂)_(r)SO₃H, (CH₂)_(r)PO₃H₂, (CH₂)_(r)PO₃RH, O(CH₂)_(r)CO₂R³, O(CH₂)_(r)SO₃H, O(CH₂)_(r)PO₃H₂, O(CH₂)_(r)PO₃RH, S(CH₂)_(r)CO₂R³, S(CH₂)_(r)SO₃H, S(CH₂)_(r)PO₃H₂, S(CH₂)_(r)PO₃RH, (CH₂)_(r)CON(R³)₂, S(CH₂)_(n)CON(R³)₂, O(CH₂)_(n)CON(R³)₂, (CH₂)_(r)NR³SO₂R, (CH₂)_(r)C(═NR³)N(R³)₂, (CH₂)_(r)NR³C(═NR³)N(R³)₂, (CH₂)_(r)NR³ (C═NR³CN)N(R³)₂, (CH₂)_(r)NR³(C═CHNO₂)N(R³)₂, (CH₂)_(r)NR³C(═NR⁵)NR³R^(5a), (CH₂)_(r)tetrazol-5-yl, and O(CH₂CH₂O)_(q)R⁴, provided that at least one X is present and is other than H; R^(a), at each occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R³, at each occurrence, is independently is independently selected from H, C₁₋₆ alkyl, and benzyl; R⁴, at each occurrence, is independently is independently selected from H, C₁₋₆ alkyl, (CH₂)_(n)aryl, and (CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; R⁵ and R^(5a) combine to form a —(CH₂)₂— or a —(CH₂)₃— group; L, at each occurrence, is independently selected from H, C₁₋₆ alkyl, —(CH₂)_(n)-phenyl, —(CH₂)_(n)—O—C₁₋₆ alkyl, and —(CH₂)_(n)—S—C₁₋₆ alkyl, wherein the phenyl group is substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃.(CH₂)_(r)CO₂R³, (CH₂)_(r)SO₃H, (CH₂)_(r)PO₃RH₂, (CH₂)_(r)PO₃RH, O(CH₂)_(r)CO₂R³, O(CH₂)_(r)SO₃H, O(CH₂)_(r)PO₃H₂, O(CH₂)_(r)PO₃RH, S(CH₂)_(r)CO₂R³, S(CH₂)_(r)SO₃H, S(CH₂)_(r)PO₃H₂, S(CH₂)_(r)PO₃RH, (CH₂)_(r)CON(R³)₂, S(CH₂)_(n)CON(R³)₂, O(CH₂)_(n)CON(R³)₂, (CH₂)_(r)NR³SO₂R, (CH₂)_(r)C(═NR³)N(R³)₂, (CH₂)_(r)NR³C(═NR³)N(R³)₂, (CH₂)_(r)NR³(C═NR³CN)N(R³)₂, (CH₂)_(r)NR³(C═CHNO₂)N(R³)₂, (CH₂)_(r)NR³C(═NR⁵)NR³R^(5a), (CH₂)_(r)tetrazol-5-yl, and O(CH₂CH₂O)_(q)R⁴; U is a counterion, but is absent when Z is O⁻; V, at each occurrence, is a counterion; Q, at each occurrence, is independently selected from H, C₁₋₆ alkyl, CO₂R, CH₂CO₂R, (CH₂)₃CO₂R, (CH₂)_(n)OR, CH₂O(CH₂CH₂O)_(q)R⁴, CH₂O(CH₂)_(n)-aryl, CH₂OC₃₋₆ alkenyl-CO₂R, CH₂NRC₃₋₆ alkenyl-CO₂R, (CH₂)_(n)O(CH₂)_(n)CO₂R, (CH₂)_(n)O(CH₂)_(n)CONH₂, (CH₂)_(n)OCH₂CHMCONRCH₂CO₂R, (CH₂)_(n)OCH₂CH(NHAc)CO₂R, (CH₂)_(n)OCH₂CH(NHR)CO₂R, (CH₂)_(n)O(CH₂)_(n)PO(OR)₂, (CH₂)_(n)O(CH₂)_(n)SO₂OR, (CH₂)_(n)O—C₂₋₆ alkenyl, (CH₂)_(n)O(CH₂)_(n)-aryl, (CH₂)_(n)O(CH₂)₂CONRCH(OR)CO₂R, (CH₂)_(n)O(CH₂)₂CONRC(R)₂CH₂SO₂OR, (CH₂)_(n)NRR, (CH₂)_(n)NR(CH₂)_(n)CO₂R, (CH₂)_(n)NR(CH₂)_(n)CONH₂, (CH₂)_(n)NRCH₂CHMCONRCH₂CO₂R, (CH₂)_(n)NRCH₂CH(NHAc)CO₂R, (CH₂)_(n)NRCH₂CH(NHR)CO₂R, (CH₂)_(n)NR(CH₂)_(n)PO(OR)₂, (CH₂)_(n)NR(CH₂)_(n)SO₂OR, (CH₂)_(n)NR(CH₂)_(n)-tetrazole, (CH₂)_(n)NR—C₂₋₆ alkenyl, (CH₂)_(n)NR(CH₂)_(n)-aryl, (CH₂)_(n)NR(CH₂)₂CONRC(R)₂CH₂SO₂OR, (CH₂)_(n)NR(CH₂)₂CONRCH(OR)CO₂R, (CH₂)_(n)NRCO(CH₂)_(n)CO₂R, and (CH₂)_(n)O(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, (CH₂)_(r)CO₂R³, (CH₂)_(r)SO₃H, (CH₂)_(r)PO₃H₂, (CH₂)_(r)PO₃RH, O(CH₂)_(r)CO₂R³, O(CH₂)_(r)SO₃H, O(CH₂)_(r)PO₃H₂, O(CH₂)_(r)PO₃RH, S(CH₂)_(r)CO₂R³, S(CH₂)_(r)SO₃H, S(CH₂)_(r)PO₃H₂, S(CH₂)_(r)PO₃RH, (CH₂)_(r)CON(R³)₂, S(CH₂)_(n)CON(R³)₂, O(CH₂)_(n)CON(R³)₂, (CH₂)_(r)NR³SO₂R, (CH₂)_(r)C(═NR³)N(R³)₂, (CH₂)_(r)NR³C(═NR³)N(R³)₂, (CH₂)_(r)NR³ (C═NR³CN)N(R³)₂, (CH₂)_(r)NR³(C═CHNO₂)N(R³)₂, (CH₂)_(r)NR³C(═NR⁵)NR³R^(5a), (CH₂)_(r)tetrazol-5-yl, and O(CH₂CH₂O)_(q)R⁴; M, at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, (CH₂)_(n)-aryl, 5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and (CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃.(CH₂)_(r)CO₂R³, (CH₂)_(r)SO₃H, (CH₂)_(r)PO₃H₂, (CH₂)_(r)PO₃RH, O(CH₂)_(r)CO₂R³, O(CH₂)_(r)SO₃H, O(CH₂)_(r)PO₃H₂, O(CH₂)_(r)PO₃RH, S(CH₂)_(r)CO₂R³, S(CH₂)_(r)SO₃H, S(CH₂)_(r)PO₃H₂, S(CH₂)_(r)PO₃RH, (CH₂)_(r)CON(R³)₂, S—(CH₂)_(n)CON(R³)₂, O—(CH₂)_(n)CON(R³)₂, (CH₂)_(r)NR³SO₂R, (CH₂)_(r)C(═NR³)N(R³)₂, (CH₂)_(r)NR³C(═NR³)N(R³)₂, (CH₂)_(r)NR³ (C═NR³CN)N(R³)₂, (CH₂)_(r)NR³(C═CHNO₂)N(R³)₂, (CH₂)_(r)NR³C(═NR⁵)NR³R^(5a), (CH₂)_(r)tetrazol-5-yl, and O(CH₂CH₂O)_(q)R⁴; Z, at each occurrence, is independently selected from O⁻, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)-aryl, and (CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; m, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; n, at each occurrence, is independently selected from 1, 2, 3, and 4; q, at each occurrence, is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; and, r, at each occurrence, is independently selected from 0, 1, 2, 3, and
 4. 2. A compound of claim 1, wherein the compound is of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein: A¹ and A² are independently selected from CH and CX; R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R¹, at each occurrence, is independently selected from (CH₂)_(m)CO₂R, C₂₋₆ alkenyl-CO₂R, (CH₂)₂CHMCONRCH₂CO₂R, CH₂CHMCONRCH₂CO₂R, CH₂CH(NHAc)CO₂R, CH₂CH(NHR)CO₂R, (CH₂)_(n)PO(OR)₂, (CH₂)₂CONRCH(OR)CO₂R, (CH₂)₂CONRC(R)₂CH₂SO₂OR, (CH₂)_(n)SO₂OR, and (CH₂)_(n)-tetrazole; X, at each occurrence, is independently selected from H, O(CH₂CH₂O)_(q)R⁴, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, O(CH₂)_(n)-aryl, NR(CH₂)_(n)-aryl, O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and NR(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴, provided that at least one X is present and is other than H; Q, at each occurrence, is independently selected from H, CH₃, (CH₂)_(n)OR, CH₂O(CH₂CH₂O)_(q)R⁴, CH₂O(CH₂)_(n)-aryl, (CH₂)_(n)O(CH₂)_(n)CONH₂, (CH₂)_(n)O—C₂₋₄ alkenyl, (CH₂)_(n)O(CH₂)_(n)-aryl, (CH₂)_(n)NRR, (CH₂)_(n)NR(CH₂)_(n)CONH₂, (CH₂)_(n)NR—C₂₋₄ alkenyl, (CH₂)_(n)NR(CH₂)_(n)-aryl, and (CH₂)_(n)O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴; R⁴, at each occurrence, is independently selected from H, C₁₋₆ alkyl, (CH₂)_(n)aryl, and (CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; q, at each occurrence, is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; and, M, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl, (CH₂)_(n)-aryl, 5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and (CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl groups are independently substituted with 0-2 groups selected from OH, OC₁₋₄ alkyl, OC₂₋₄ alkenyl, OC₂₋₄ alkynyl, halogen, nitro, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, and O(CH₂CH₂O)_(q)R⁴.
 3. A compound of claim 1, wherein the compound is selected from Tables Ia-Id, or a stereoisomer or pharmaceutically acceptable salt thereof: Table Ia

Ex. # X¹ X² R¹ 1 H N(Et)₂ CO₂Et 2 H N(Et)₂ CO₂H 3 H N(Et)₂ CH₂CO₂Et 4 H N(Et)₂ CH₂CO₂H 5 H N(Et)₂ CH₂CH═CHCO₂H 6 H N(Et)₂ CH₂CH═CHCO₂Et 7 H N(Et)₂ CH₂PO(OH)₂ 8 H N(Et)₂ CH₂PO(OEt)₂ 9 N(Et)₂ H CO₂Et 10 N(Et)₂ H CO₂H 11 N(Et)₂ H CH₂CO₂Et 12 N(Et)₂ H CH₂CO₂H 13 N(Et)₂ H CH₂PO(OH)₂ 14 N(Et)₂ H CH₂PO(OEt)₂

Table Ib

Ex. # X¹ X² R¹ 1 H N(Et)₂ CO₂Et 2 H N(Et)₂ CO₂H 3 H N(Et)₂ CH₂CO₂Et 4 H N(Et)₂ CH₂CO₂H 5 H N(Et)₂ CH₂CH═CHCO₂H 6 H N(Et)₂ CH₂CH═CHCO₂Et 7 H N(Et)₂ CH₂PO(OH)₂ 8 H N(Et)₂ CH₂PO(OEt)₂ 9 N(Et)₂ H CO₂Et 10 N(Et)₂ H CO₂H 11 N(Et)₂ H CH₂CO₂Et 12 N(Et)₂ H CH₂CO₂H 13 N(Et)₂ H CH₂PO(OH)₂ 14 N(Et)₂ H CH₂PO(OEt)₂

TABLE Ic

Ex. # X¹ X² R¹ 1 H N(Et)₂ CO₂Et 2 H N(Et)₂ CO₂H 3 H N(Et)₂ CH₂CO₂Et 4 H N(Et)₂ CH₂CO₂H 5 H N(Et)₂ CH₂CH═CHCO₂H 6 H N(Et)₂ CH₂PO(OH)₂ 7 H N(Et)₂ CH₂PO(OEt)₂ 8 N(Et)₂ H CO₂Et 9 N(Et)₂ H CO₂H 10 N(Et)₂ H CH₂CO₂Et 11 N(Et)₂ H CH₂CO₂H 12 N(Et)₂ H CH₂PO(OH)₂ 13 N(Et)₂ H CH₂PO(OEt)₂

TABLE Id

Ex. # X¹ X² R¹ 1 H N(Et)₂ CO₂Et 2 H N(Et)₂ CO₂H 3 H N(Et)₂ CH₂CO₂Et 4 H N(Et)₂ CH₂CO₂H 5 H N(Et)₂ CH₂CH═CHCO₂H 6 H N(Et)₂ CH₂CH═CHCO₂Et 7 H N(Et)₂ CH₂PO(OH)₂ 8 H N(Et)₂ CH₂PO(OEt)₂ 9 N(Et)₂ H CO₂Et 10 N(Et)₂ H CO₂H 11 N(Et)₂ H CH₂CO₂Et 12 N(Et)₂ H CH₂CO₂H 13 N(Et)₂ H CH₂PO(OH)₂ 14 N(Et)₂ H CH₂PO(OEt)₂.


4. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
 5. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of claim 2 and a pharmaceutically acceptable carrier.
 6. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of claim 3 and a pharmaceutically acceptable carrier.
 7. A compound of claim 3, wherein the compound is selected from Table Ia or a stereoisomer or pharmaceutically acceptable salt thereof.
 8. A compound of claim 3, wherein the compound is selected from Table Ib or a stereoisomer or pharmaceutically acceptable salt thereof.
 9. A compound of claim 3, wherein the compound is selected from Table Ic or a stereoisomer or pharmaceutically acceptable salt thereof.
 10. A compound of claim 3, wherein the compound is selected from Table Id or a stereoisomer or pharmaceutically acceptable salt thereof.
 11. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of claim 3 selected from Table Ia and a pharmaceutically acceptable carrier.
 12. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of claim 3 selected from Table Ib and a pharmaceutically acceptable carrier.
 13. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of claim 3 selected from Table Ic and a pharmaceutically acceptable carrier.
 14. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of claim 3 selected from Table Id and a pharmaceutically acceptable carrier. 